Heterocyclo-alkylsulfonyl pyrazoles as anti-inflammatory/analgesic agents

ABSTRACT

The present invention relates to compounds of the formula 
                 
 
wherein R 1 , R 3 , R 5 , R 6 , and A are defined as in the specification, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the invention are useful in the treatment of inflammation and other inflammation associated disorders, such as osteoarthritis, rheumatoid arthritis, colon cancer and Alzheimer&#39;s disease, in mammals (preferably humans, dogs, cats and livestock).

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority of U.S. provisional application Ser.No. 60/303,169, filed Jul. 5, 2001.

BACKGROUND OF THE INVENTION

This invention relates to heterocyclo-alkylsulfonyl pyrazoles, methodsof treatment and pharmaceutical compositions for the treatment ofcyclooxygenase mediated diseases, such as arthritis, neurodegenerationand colon cancer, in mammals, preferably humans, dogs, cats orlivestock.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used intreating pain and the signs and symptoms of arthritis because of theiranalgesic and anti-inflammatory activity. Common NSAIDs work by blockingthe activity of cyclooxygenase (COX), an enzyme that convertsarachidonic acid into prostanoids. Two forms of COX are now known, aconstitutive isoform (COX-1) and an inducible isoform (COX-2) of whichexpression is upregulated at sites of inflammation (Vane, J. R.;Mitchell, et. al., Proc. Natl. Acad. Sci. USA, 1994, 91, 2046). COX-1appears to play a physiological role and to be responsible forgastrointestinal and renal protection. On the other hand, COX-2 appearsto play a pathological role and is believed to be the predominantisoform present in inflammation conditions. The therapeutic use ofconventional NSAIDs is, however, limited due to drug associated sideeffects, including life threatening ulceration and renal toxicity.

COX is also known as prostaglandin G/H synthase (PGHS). Prostaglandins,especially prostaglandin E₂ (PGE₂), a predominant eicosanoid detected ininflammation conditions, are mediators of pain, fever and other symptomsassociated with inflammation. A pathological role for prostaglandins hasbeen implicated in a number of human diseases including rheumatoidarthritis, osteoarthritis, pyrexia, asthma, bone resorption,cardiovascular diseases, dysmenorrhea, premature labour, nephritis,nephrosis, atherosclerosis, hypotension, shock, pain, cancer andAlzheimer. Compounds that selectively inhibit the biosynthesis ofprostaglandins by intervention of the induction phase of the inducibleenzyme COX-2 and/or by intervention of the activity of the enzyme COX-2on arachidonic acid would provide alternate therapy to the use of NSAIDsor corticosteriods in that such compounds would exert anti-inflammatoryeffects without the adverse side effects associated with COX-1inhibition.

A variety of sulfonylbenzene compounds which inhibit COX have beendisclosed in patent publications (WO 97/11704, WO 97/16435, WO 97/14691,WO 96/19469, WO 96/36623, WO 96/03392, WO 96/03387, WO 96/19469, WO96/08482, WO 95/00501, WO 95/15315, WO 95/15316, WO 95/15317, WO95/15318, WO 97/13755, EP 0799523, EP 418845, EP 554829 and EP 1099695).

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula

wherein

is a heterocycle selected from the group consisting of

m is 0, 1 or 2, preferably m is 2;

X is CR⁷ or N, preferably CR⁷ wherein R⁷is hydrogen;

R¹ is hydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylcarbonyl, formyl,formamidyl, cyano, nitro, hydroxycarbonyl, (C₁C₆)alkoxycarbonyl,(C₂-C₉)heteroarylcarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₂-C₉)heteroarylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, or (C₁-C₆)alkylcarbonyl-N(R²)—;

wherein each of said R¹ (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy;

R² is hydrogen or (C₁-C₆)alkyl;

R³ is (C₁-C₆)alkylthio, (C₃-C₇)carbocyclylthio, C₆-C₁₀)arylthio,(C₂-C₉)heteroarylthio, (C₁-C₆)alkyl-S(═O), (C₆-C₁₀)aryl-S(═O),(C₂-C₉)heteroaryl-S(═O), (C₁-C₆)alkyl-SO₂-, (C₆-C₁₀)aryl-SO₂—,(C₂-C₉)heteroaryl-SO₂—, (C₁-C₆)alkyl-SO₂-amino,(C₃-C₇)carbocyclyl-SO₂-amino, (C₆-C₁₀)aryl-SO₂-amino,(C₂-C₉)heteroaryl-SO₂-amino, amino-SO₂—, N—(C₁-C₆)alkylamino-SO₂—,N,N—[(C₁-C₆)alkyl]₂amino-SO₂—, N—(C₃-C₇)carbocyclylamino-SO₂—,N—(C₆-C₁₀)arylamino-SO₂—, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino-SO₂—,N—(C₂-C₉)heteroarylamino-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, orN—(C₂-C₉)heteroarylamino;

wherein each of said R³ (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy;

R⁴ is (C₁-C₆)alkyl optionally substituted by hydroxy or one to threehalo atoms, such as fluoro atoms;

R⁵ is hydrogen, halo, hydroxy, mercapto, (C₁-C₆)alkyl, (C₁-C₆)alkoxyoptionally substituted with one to three halo (such as fluoro) atoms,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, cyano, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylcarbonyloxy, hydroxycarbonyl,(C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆₎alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido, or(C₁-C₆)alkylthio;

wherein each of said R⁵ (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₈-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy;

R⁶ is selected from the group consisting of:

(a) phenyl optionally substituted by one to three, preferably one,substituents independently selected from the group consisting of halo(preferably fluoro), hydroxy, cyano, mercapto, hydroxycarbonyl, nitro,(C₁-C₆)alkyl (preferably methyl), (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; preferably halo, most preferably one fluoro atom,or (C₁-C₆)alkyl, most preferably methyl;

(b) phenyl fused to a saturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring;

wherein either of said phenyl or said fused saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring is optionallysubstituted by one to two substituents per ring, wherein saidsubstituents are independently selected from the group consisting ofhalo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy,—OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

(c) phenyl fused to a saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the group consisting of —N═, —NR²—, —S— and—O—;

wherein either of said phenyl or said fused saturated, partiallysaturated or aromatic (5- to 6-membered)-heterocyclyl is optionallysubstituted with one to two substituents per ring;

wherein said substituents are independently selected from the groupconsisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N-—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

(d) (3- to 7-membered)-carbocyclic optionally containing one or twodouble bonds, preferably the (3- to 7-membered)-carbocyclic contains nodouble bonds;

wherein said (3- to 7-membered)-carbocyclic may also be optionallysubstituted by one to three substituents independently selected from thegroup consisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl,nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

(e) (5- to 7-membered)-carbocyclic fused to a saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring;

wherein said (5- to 7-membered)-carbocyclic may optionally contain oneor two double bonds;

wherein either of said (5- to 7-membered)-carbocyclic or said fusedsaturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring is optionally substituted by one to twosubstituents per ring, wherein said substituents are independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

(f) (5- to 7-membered)-carbocyclic fused to a saturated, partiallysaturated or aromatic (5- to 6-membered)-heterocyclyl containing one totwo ring heteroatoms independently selected from the group consisting of—N═, —NR²—, —S— and —O—;

wherein said (5- to 7-membered)-carbocyclic may optionally contain oneor two double bonds;

wherein either of said (5- to 7-membered)-carbocyclic or said fusedsaturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is optionally substituted with one to twosubstituents per ring;

wherein said substituents are independently selected from the groupconsisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

(g) saturated, partially saturated or aromatic, preferably aromatic, (5-to 6-membered)-heterocyclyl containing one to four, preferably one, ringheteroatom(s) independently selected from the groups consisting of —N═,—NR₂—, —O—, and —S—, preferably selected from the group consisting of—O—, and —S—;

wherein said (5- to 6-membered)-heterocyclyl is optionally substitutedby one to three substituents independently selected from the groupconsisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; preferably said (5- to 6-membered)-heterocyclyl isunsubstituted;

(h) saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the group consisting of —N═, —NR²—, —S— and—O—;

wherein said saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is fused to a saturated, partially saturated oraromatic (5- to 7-membered)-carbocyclic ring;

wherein either of said saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl ring or said fused saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring is optionallysubstituted by one to two substituents per ring;

wherein said substituents are independently selected from the groupconsisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; and

(i) saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the group consisting of —N═, —NR²—, —S—, and—O—;

wherein said saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is fused to a saturated, partially saturated oraromatic (5- to 6-membered)-heterocyclyl containing one to two ringheteroatoms independently selected from the group consisting of —N═,—NR²—, —S— and —O—;

wherein either of said saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl or said fused saturated, partially saturated oraromatic (5- to 6-membered)-heterocyclyl is optionally substituted withone to twosubstituents per ring;

wherein said substituents are independently selected from the groupconsisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

wherein each of said R¹ (a), (b), (c), (d), (e), (f), (g), (h), or (i)(C₁-C₆)alkyl group wherever they occur may optionally be substitutedwith one to three substituents independently selected from the groupconsisting of halo, hydroxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl, formamidyl,(C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro, hydroxycarbonyl,(C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino, N—(C₆C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy;

R⁷ is hydrogen, halo, hydroxy, mercapto, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,optionally substituted with one to three halogen atoms, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, cyano, formyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylcarbonyloxy, hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido, nitro, or(C₁-C₆)alkylthio;

wherein each of said R⁷ (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy;

and the pharmaceutically acceptable salts thereof.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula I. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, acid citrate, tartrate, bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, para-toluenesulfonate and pamoate[i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula I. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula I that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cations(e.g., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine (meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The compounds of this invention include all stereoisomers (e.g., cis andtrans isomers) and all optical isomers of compounds of the formula I(e.g., R and S enantiomers), as well as racemic, diastereomeric andother mixtures of such isomers.

The compounds of the invention also exist in different tautomeric forms.This invention relates to all tautomers of formula I.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof.

Unless otherwise indicated, the alkyl, referred to herein, as well asthe alkyl moieties of other groups referred to herein (e.g., alkoxy),may be linear or branched (such as methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, secondary-butyl, tertiary-butyl).

Unless otherwise indicated, halo includes fluoro, chloro, bromo or iodo.

As used herein, the term “alkenyl” means straight or branched chainunsaturated radicals of 2 to 6 carbon atoms, including, but not limitedto ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, or 2-butenyl.

As used herein, the term “alkynyl” is used herein to mean straight orbranched hydrocarbon chain radicals of 2 to 6 carbon atoms having onetriple bond including, but not limited to, ethynyl, propynyl, orbutynyl.

As used herein, the term “alkoxy” refers to O-alkyl groups, whereinalkyl is as defined above.

As used herein, the term “alkoxycarbonyl” refers to an alkoxy radical asdescribed above connected to a carbonyl group (>C═O), which, in turn,serves as the point of attachment.

As used herein, the term “carbocyclyl” refers to a mono or bicycliccarbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl andbicyclo[5.2.0]nonanyl, etc.); optionally containing 1 or 2 double bonds.

As used herein, the term “amido” refers to aminocarbonyl- or carbamoyl-or NH₂—(C═O)— moiety.

As used herein the term “aryl” means aromatic radicals such as phenyl,naphthyl, tetrahydronaphthyl, or indanyl.

As used herein the term “heteroaryl” refers to aromatic groupscontaining one or more heteroatoms (O, S, or N). A multicyclic groupcontaining one or more heteroatoms wherein at least one ring of thegroup is aromatic is a s“heteroaryl” group. The heteroaryl groups ofthis invention can also include ring systems substituted with one ormore oxo moieties. Examples of heteroaryl groups include, but are notlimited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl,isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl,indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,isoindolyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl,dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl,tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, andazaindolyl.

The term “heterocyclic” as used herein refers to a cyclic groupcontaining 2-9 carbon atoms and 1-4 hetero atoms selected from N, O, orS. Examples of such rings include furyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, thiazolyl,isothiazolyl, oxadiazolyl, oxatriazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, and the like. Examples of saidmonocyclic saturated or partially saturated ring systems aretetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl,imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl,isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,1,3-pyrazolidin-1-yl, thiomorpholine, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazine, morpholine,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl,1,2,5-oxathiazin-4-yl and the like; optionally substituted by 1 to 3suitable substituents as defined below such as fluoro, chloro,trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or (C₁-C₆)alkyl.

The term “phenyl fused to a saturated, partially saturated or aromatic(5- to 7-membered)-carbocyclic ring”, as used herein, unless otherwiseindicated, means a bicyclic group having a first phenyl ring covalentlybound to the pyrazole nucleus and wherein said first ring is fused to asecond ring comprising a 5 to 7 membered carbocycle, wherein the 5 to 7members include the carbon atoms common to both rings. Examples of suchrings include tetralin-5-yl, tetralin-6-yl, 2,3-dihydro-inden-4-yl,2,3-dihydro-inden-5-yl, inden-4-yl, inden-5-yl,7,8-dihydro-naphthalen-1-yl, 7,8-dihydro-naphthalen-2-yl,5,6-dihydro-naphthalen-1-yl, 5,6-dihydro-naphthalen-2-yl,5,8-dihydro-naphthalen-1-yl, 5,8-dihydro-naphthalen-2-yl,naphthalen-1-yl, naphthalen-2-yl,5-(6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl)-,5-(8,9-dihydro-7H-benzocyclohepten-1-yl)-,5-(6,7-dihydro-5H-benzocyclohepten-1-yl)-,5-(7H-benzocyclohepten-1-yl)-, 5-(5H-benzocyclohepten-1-yl)-,5-(9H-benzocyclohepten-1-yl)-,5-(6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-,5-(6,7-dihydro-5H-benzocyclohepten-2-yl)-,5-(8,9-dihydro-7H-benzocyclohepten-2-yl)-,5-(5H-benzocyclohepten-2-yl)-, 5-(9H-benzocyclohepten-2-yl )-, or5-(7H-benzocyclohepten-2-yl )-.

The term “phenyl fused to a saturated, partially saturated or aromatic(5- to 6-membered)-heterocyclic ring”, as used herein, unless otherwiseindicated, means a bicyclic group having a first phenyl ring covalentlybound to the pyrazole nucleus and wherein said first ring is fused to asecond ring comprising a (5- to 6-membered)-heterocyclic ring, whereinthe 5 to 6 members include the carbon atoms common to both rings. Saidsecond ring comprises a saturated, partially saturated or aromatic (5-to 6-membered)-heterocyclic ring. Examples of such rings includequinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl,isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl,quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl,cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl, cinnolin-8-yl,4H-1,4-benzoxazin-5-yl, 4H-1,4-benzoxazin-6-yl, 4H-1,4-benzoxazin-7-yl,4H-1,4-benzoxazin-8-yl, 4H-1,4-benzthiazin-5-yl,4H-1,4-benzthiazin-6-yl, 4H-1,4-benzthiazin-7-yl,4H-1,4-benzthiazin-8-yl, 1,4H-1,4-benzdiazin-5-yl,1,4H-1,4-benzdiazin-6-yl, 1,4H-1,4-benzdiazin-7-yl,1,4H-1,4-benzdiazin-8-yl, indol-4-yl, indol-5-yl, indol-6-yl,indol-7-yl, benzo(b)thiophen-4yl, benzo(b)thiophen-5-yl,benzo(b)thiophen-6-yl, benzo(b)thiophen-7-yl, benzofuran-4-yl,benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzisoxazol-4-yl,benzisoxazol-5-yl, benzisoxazol-6-yl, benzisoxazol-7-yl,benzoxazol-4-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl andbenzoxazol-7-yl. Preferred fused phenylheteroaryl rings includequinolinyl, isoquinolinyl, indolyl, benzo(b)thiophenyl, or benzofuranyl.

The term “(3- to 7-membered)-carbocyclic”, as used herein, unlessotherwise indicated, means a monocyclic group containing 3 to 7 carbonatoms and optionally containing 1 or 2 double bonds. Examples of suchrings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptanyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.

The term “(5- to 7-membered)-carbocyclic”, as used herein, unlessotherwise indicated, means a monocyclic group containing 5 to 7 carbonatoms and optionally containing 1 or 2 double bonds. Examples of suchrings include cyclopentyl, cyclohexyl, cycloheptanyl, cyclopentenyl,cyclohexenyl or cycloheptenyl.

The term “(5- to 7-membered)-carbocyclic fused to a saturated orpartially saturated (5- to 7-membered)-carbocyclic ring”, as usedherein, unless otherwise indicated, means a bicyclic group having afirst carbocyclic ring covalently bound to the pyrazole nucleus andwherein said first ring is fused to a second ring comprising a 5 to 7membered carbocycle, wherein the 5 to 7 members include the carbon atomscommon to both rings and wherein said second ring may contain 1, 2 or 3double bonds. Examples of such rings, wherein the fusion is so calledortho fused, include tetralin-1-yl, tetralin-2-yl,hexahydronaphthalen-1-yl, hexahydronaphthalen-2-yl,octahydronaphthalen-1-yl, octahydronaphthalen-2-yl, decalin-1-yl,decalin-2-yl, 4,5,6,7-tetrahydro-indan-4-yl,4,5,6,7-tetrahydro-indan-5-yl, 4,5,6,7,8,9-hexahydro-indan-4-yl,4,5,6,7,8,9-hexahydro-indan-5-yl, 4,5,6,7-tetrahydro-inden-4-yl,4,5,6,7-tetrahydro-inden-5-yl, 4,5,6,7,8,9-hexahydro-inden-4-yl,4,5,6,7,8,9-hexahydro-inden-5-yl, pentalan-1-yl, pentalan-2-yl , 4,5dihydro-pentalan-1-yl, 4,5 dihydro-pentalan-2-yl,4,5,6,7tetrahydro-pentalan-1-yl, 4,5,6,7 tetra-pentalan-2-yl,benzocycloheptan-5-yl, benzocycloheptan-6-yl and the like. Examples ofsuch bicyclic rings that are not ortho fused includebicyclo[3.2.1]-octan-2-yl, bicyclo[3.2.1]-octan-3-yl, bicyclo[5.2.0]nonan-2-yl, bicyclo [5.2.0]nonan-3-yl, bicyclo [5.2.0]nonan-4-yl,bicyclo [4.3.2]undecan-7-yl, bicyclo [4.3.2]undecan-8-yl, bicyclo[4.3.2]undecan-9-yl, bicyclo[2.2.2]-octan-2-yl,bicyclo[2.2.2]-octan-3-yl, bicyclo[2.2.1]-heptan-2-yl,bicyclo[3.1.1]-heptan-2-yl, or borneol-2-yl.

The term “(5- to 7-membered)carbocyclic fused to a saturated, partiallysaturated or aromatic (5- to 6-membered)-heterocyclic”, as used herein,unless otherwise indicated, means a bicyclic group having a firstcarbocyclic ring covalently bound to the pyrazole nucleus and whereinsaid first ring is fused to a second ring comprising a 5 to 6 memberedheterocyclic ring, wherein said second 5 to 6 members include the atomscommon to both rings. Said second ring comprises a saturated, partiallysaturated or aromatic (5- to 6-membered)-heterocyclic ring. Examples ofsaid bicyclic ring systems are 5,6,7,8 tetrahydro-quinolin-5-yl, 5,6,7,8tetrahydro-quinolin-6-yl, 5,6,7,8 tetrahydro-quinolin-7-yl, 5,6,7,8tetrahydro-quinolin-8-yl, 5,6,7,8 tetrahydro-isoquinolin-5-yl, 5,6,7,8tetrahydro-isoquinolin-6-yl, 5,6,7,8 tetrahydro-isoquinolin-7-yl,5,6,7,8 tetrahydro-isoquinolin-8-yl, 5,6,7,8 tetrahydro-quinazolin-5-yl,5,6,7,8 tetrahydro-quinazolin-6-yl, 5,6,7,8 tetrahydro-quinazolin-7-yl,5,6,7,8 tetrahydro-quinazolin-8-yl, 5,6,7,8tetrahydro-4H-1,4-benzoxazin-5-yl, 5,6,7,8tetrahydro-4H-1,4-benzoxazin-6-yl, 5,6,7,8tetrahydro-4H-1,4-benzoxazin-7-yl, 5,6,7,8tetrahydro-4H-1,4-benzoxazin-8-yl, 5,6,7,8tetrahydro-4H-1,4-benzthiazin-5-yl, 5,6,7,8tetrahydro-4H-1,4-benzthiazin-6-yl, 5,6,7,8tetrahydro-4H-1,4-benzthiazin-7-yl, 5,6,7,8tetrahydro-4H-1,4-benzthiazin-8-yl, 5,6,7,8tetrahydro-1,4H-1,4-benzdiazin-5-yl, 5,6,7,8tetrahydro-1,4H-1,4-benzdiazin-6-yl, 5,6,7,8tetrahydro-1,4H-1,4-benzdiazin-7-yl, 5,6,7,8tetrahydro-1,4H-1,4-benzdiazin-8-yl, 4,5,6,7 tetrahydro-indol-4-yl,4,5,6,7 tetrahydro indol-5-yl, 4,5,6,7 tetrahydro-indol-6-yl, 4,5,6,7tetrahydro-indol-7-yl, 4,5,6,7 tetrahydro-benzo(b)thiophen-4-yl, 4,5,6,7tetrahydro-benzo(b)thiophen-5-yl, 4,5,6,7tetrahydro-benzo(b)thiophen-6-yl, 4,5,6,7tetrahydro-benzo(b)thiophen-7-yl, 4,5,6,7 tetrahydro-benzofuran-4-yl,4,5,6,7 tetrahydro-benzofuran-5-yl, 4,5,6,7 tetrahydro-benzofuran-6-yl,4,5,6,7 tetrahydro-benzofuran-7-yl, 4,5,6,7tetrahydro-benzisoxazol-4-yl, 4,5,6,7 tetrahydro-benzisoxazol-5-yl,4,5,6,7 tetrahydro-benzisoxazol-6-yl, 4,5,6,7tetrahydro-benzisoxazol-7-yl, 4,5,6,7 tetrahydro-benzoxazol-4-yl,4,5,6,7 tetrahydro-benzoxazol-4-yl, 4,5,6,7 tetrahydro-benzoxazol-5-yl,4,5,6,7 tetrahydro-benzoxazol-6-yl, or 4,5,6,7tetrahydro-benzoxazol-7-yl.

The term “saturated, partially saturated or aromatic (5- to6-membered)heterocyclic containing 1 to 4 ring heteroatoms independentlyselected from —N═, —NR²—, —O—, or —S—”, as used herein, unless otherwiseindicated, means a monocyclic (5- to 6-membered)heterocyclic ringcovalently bound to the pyrazole nucleus. Said ring may contain optionaldouble bonds so as to include saturated, partially saturated or aromatic(5- to 6-membered)-heterocyclic rings. Examples of the monocyclicaromatic ring systems are furyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, thiazolyl,isothiazolyl, oxadiazolyl, oxatriazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, and the like. Examples of saidmonocyclic saturated or partially saturated ring systems arepiperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl,piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidine,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,thiomorpholine, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl,tetrahydrothiadiazine, morpholine, 1,2-tetrahydrodiazin-2-yl,1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl, or 1,2,5-oxathiazin-4-yl.

The term “saturated, partially saturated or aromatic (5- to6-membered)heterocyclic fused to a saturated, partially saturated oraromatic (5- to 7-membered)-carbocyclic ring”, as used herein, unlessotherwise indicated, means a bicyclic group having a first (5- to6-membered)heterocyclic ring covalently bound to the pyrazole nucleusand wherein said first ring is fused to a second ring comprising a 5 to6 membered heterocyclic ring, wherein said second 5 to 6 members includethe atoms common to both rings. Said first and second rings comprisesaturated, partially saturated or aromatic (5- to6-membered)-heterocyclic rings. Examples of said bicyclic ring systemsare indolidin-4-yl, indolidin-5-yl, quinolidin-5-yl, quinolidin-6-yl,quinolidin-7-yl, quinolidin-8-yl, isoquinolidin-5-yl,isoquinolidin-6-yl, isoquinolidin-7-yl, isoquinolidin-8-yl,quinazolidin-5-yl, quinazolidin-6-yl, quinazolidin-7-yl,quinazolidin-8-yl, benzofuran-2-yl, benzofuran-3-yl, isobenzofuran-1-yl,isobenzofuran-3-yl, benzothiophen-2-yl, benzothiophen-3-yl, indol-2-yl,indol-3-yl, isoindol-1-yl, isoindol-3-yl, cyclopentapyrid-2-yl,cyclopentapyrid-3-yl, benzoxazol-2-yl, or cinnolin-4-yl.

The term “saturated, partially saturated or aromatic (5- to6-membered)heterocyclic fused to a saturated, partially saturated oraromatic (5- to 6-membered)-heterocyclic” as used herein, unlessotherwise indicated, means a bicyclic heterocyclic group having a firstring covalently bound to the pyrazole nucleus and containing five to sixring atoms comprising one to two heteroatoms each independently selectedfrom —N═, —NH—, —[N—(C₁-C₄)alkyl]-, —O— and —S—; wherein said first ringis fused to a second ring comprising a 5 to 6 membered heterocyclicring, wherein said second 5 to 6 members include the atoms common toboth rings. Said second ring comprises a saturated, partially saturatedor aromatic (5- to 6-membered)-heterocyclic ring. Examples of saidbicyclic ring systems are pyrano[3,4b]pyrrolyl, pyrano[3,2b]pyrrolyl,pyrano[4,3b]pyrrolyl, purin-2-yl, purin-6-yl, purin-7-yl, purin-8-yl,pteridin-2-yl, pyrido[3,4b]pyridyl, pyrido[3,2b]pyridyl,pyrido[4,3b]pyridyl, or naphthyridinyl.

An embodiment and a preferred group of compounds of the presentinvention includes compounds of formula 1, referred to as the IA1 groupof compounds, wherein said compounds have the formula

wherein X is CR⁷ or N, preferably CR⁷ wherein R⁷ is hydrogen; andwherein m is preferably 2.

A preferred group of compounds of the present invention includescompounds of formula I, referred to as the IA2 group of compounds,wherein said compounds have the formula

wherein X is CR⁷ or N, wherein X is CR⁷ or N, preferably CR⁷ wherein R⁷is hydrogen hydrogen; and wherein m is preferably 2.

An embodiment of the present invention includes compounds of formula I,referred to as the IA3 group of compounds, wherein said compounds havethe formula

wherein R¹, R³, R⁴, R⁵ and R⁶ are as defined above hydrogen; and whereinm is preferably 2.

An embodiment of the present invention includes compounds of formula I,referred to as the IA4 group of compounds, wherein said compounds havethe formula

wherein R¹, R³, R⁴, R⁵ and R⁶ are as defined above hydrogen; and whereinm is preferably 2.

An embodiment of the present invention includes compounds of formula I,referred to as the IA5 group of compounds, wherein said compounds havethe formula

wherein R¹, R³, R⁴, R⁵ and R⁶ are as defined above hydrogen; and whereinm is preferably 2.

An embodiment of the present invention includes compounds of formula I,referred to as the IA6 group of compounds, wherein said compounds havethe formula

wherein R¹, R³, R⁴, R⁵ and R⁶ are as defined above hydrogen; and whereinm is preferably 2.

An embodiment and a preferred group of compounds of the presentinvention includes compounds of formula I, referred to as the R⁶ (a)group of compounds, wherein R⁶ is

(a) phenyl optionally substituted by one to three, preferably one,substituents independently selected from the group consisting of halo(preferably fluoro), hydroxy, cyano, mercapto, hydroxycarbonyl, nitro,(C₁-C₆)alkyl (preferably methyl), (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; preferably halo, most preferably one fluoro atom,or (C₁-C₆)alkyl, most preferably methyl;

wherein each of said R⁶ (a) (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

A preferred embodiment of the R⁶ (a) group of compounds includescompounds of formula I wherein R⁶ is phenyl optionally substituted byone to three, preferably one, substituents independently selected fromthe group consisting of halo, most preferably chloro, or (C₁-C₆)alkyl,most preferably methyl;

wherein each of said R⁶ (a) (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₅)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

Another preferred embodiment of the R⁶ (a) group of compounds includescompounds of formula I wherein R⁶ is phenyl optionally substituted withone to three, preferably one, halo, preferably chloro, or one to three,preferably one, (C₁-C₆)alkyl, preferably methyl.

Another preferred embodiment of the R⁶ (a) group of compounds includescompounds of formula I wherein R⁶ is unsubstituted phenyl.

An embodiment of the present invention includes compounds of formula I,referred to as the R⁶ (b) group of compounds, wherein R⁶ is

(b) phenyl fused to a saturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring;

wherein either of said phenyl or said fused saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring is optionallysubstituted by one to two substituents per ring, wherein saidsubstituents are independently selected from the group consisting ofhalo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy,—OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

wherein each of said R⁶ (b) (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

An embodiment of the present invention includes compounds of formula I,referred to as the R⁶ (c) group of compounds, wherein R⁶ is

(c) phenyl fused to a saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the group consisting of —N═, —NR²—, —S— and—O—;

wherein either of said phenyl or said fused saturated, partiallysaturated or aromatic (5- to 6-membered)-heterocyclyl is optionallysubstituted with one to two substituents per ring;

wherein said substituents are independently selected from the groupconsisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆) alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

wherein each of said R⁶ (c) (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbony-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

An embodiment of the present invention includes compounds of formula I,referred to as the R⁶ (d) group of compounds, wherein R⁶ is

(d) (3- to 7-membered)-carbocyclic optionally containing one or twodouble bonds, preferably the (3- to 7-membered)-carbocyclic contains nodouble bonds;

wherein said (3- to 7-membered)-carbocyclic may also be optionallysubstituted by one to three substituents independently selected from thegroup consisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl,nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

wherein each of said R⁶ (d) (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

Another embodiment of the R⁶ (d) group of compounds includes compoundsof formula I wherein R⁶ is cyclohexyl optionally substituted by onesubstituent independently selected from the group consisting of halo,such as chloro, or (C₁-C₆)alkyl, such as methyl.

An embodiment of the present invention includes compounds of formula I,referred to as the R⁶ (e) group of compounds, wherein R⁶ is

(e) (5- to 7-membered)-carbocyclic fused to a saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring;

wherein said (5- to 7-membered)-carbocyclic may optionally contain oneor two double bonds;

wherein either of said (5- to 7-membered)-carbocyclic or said fusedsaturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring is optionally substituted by one to twosubstituents per ring, wherein said substituents are independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

wherein each of said R⁶ (e) (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

An embodiment of the present invention includes compounds of formula I,referred to as the R⁶ (f) group of compounds, wherein R⁶ is

(f) (5- to 7-membered)-carbocyclic fused to a saturated, partiallysaturated or aromatic (5- to 6-membered)-heterocyclyl containing one totwo ring heteroatoms independently selected from the group consisting of—N═, —NR²—, —S— and —O—;

wherein said (5- to 7-membered)-carbocyclic may optionally contain oneor two double bonds;

wherein either of said (5- to 7-membered)-carbocyclic or said fusedsaturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is optionally substituted with one to twosubstituents per ring;

wherein said substituents are independently selected from the groupconsisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₁-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

wherein each of said R⁶ (f) (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

An embodiment of the present invention includes compounds of formula I,referred to as the R⁶ (g) group of compounds, wherein R⁶ is

(g) saturated, partially saturated or aromatic, preferably aromatic, (5-to 6-membered)-heterocyclyl containing one to four, preferably one, ringheteroatom(s) independently selected from the groups consisting of —N═,—NR²—, —O—, and —S—, preferably selected from the group consisting of—O—, and —S—;

wherein said (5- to 6-membered)-heterocyclyl is optionally substitutedby one to three substituents independently selected from the groupconsisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; preferably said (5- to 6-membered)-heterocyclyl isunsubstituted;

wherein each of said R⁶ (g) (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

Another embodiment of the R⁶ (g) group of compounds includes compoundsof formula I wherein R⁶ is saturated, partially unsaturated or aromatic,preferably aromatic, (5- to 6-membered), preferably 5-membered,heterocyclyl containing one to four preferably one, ring heteroatoms,independently selected from the groups consisting of —N═, —NR²—, —O—,and —S—, preferably selected from the group consisting of —O—, and —S—;

wherein said (5- to 6-membered)-heterocyclyl is optionally substitutedby one to three substituents, preferably no substituents, independentlyselected from the group consisting of halo, such as chloro, or(C₁-C₆)alkyl, such as methyl;

wherein each of said R⁶ (g) (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C6)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

Another embodiment of the R⁶ (g) group of compounds includes compoundsof formula I wherein R⁶ is aromatic (5- to 6-membered)-heterocyclylcontaining one to two, preferably one, ring heteroatoms independentlyselected from the groups consisting of —N═, —NR²—, —O—, and —S—;preferably selected from the group consisting of —O—, and —S—;

wherein said (5- to 6-membered)-heterocyclyl is substituted by one tothree, preferably one, halo, preferably chloro, or one to three,preferably one, (C₁-C₆)alkyl, preferably methyl.

Other preferred embodiment of the R⁶ (g) group of compounds includescompounds of formula I wherein R⁶ is unsubstituted aromatic (5- to6-membered)-, more preferably (5-membered)-heterocyclyl, such asthienyl, most preferably 2-thienyl, or furanyl, most preferably2-furanyl.

An embodiment of the present invention includes compounds of formula I,referred to as the R⁶ (h) group of compounds, wherein R⁶ is

(h) saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the group consisting of —N═, —NR²—, —S— and—O—;

wherein said saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is fused to a saturated, partially saturated oraromatic (5- to 7-membered)-carbocyclic ring;

wherein either of said saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl ring or said fused saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring is optionallysubstituted by one to two substituents per ring;

wherein said substituents are independently selected from the groupconsisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

wherein each of R⁶ (h) (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryoxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

An embodiment of the present invention includes compounds of formula I,referred to as the R⁶ (i) group of compounds, wherein R⁶ is

(i) saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the group consisting of —N═, —NR²—, —S—, and—O—;

wherein said saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is fused to a saturated, partially saturated oraromatic (5- to 6-membered)-heterocyclyl containing one to two ringheteroatoms independently selected from the group consisting of —N═,—NR²—, —S— and —O—;

wherein either of said saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl or said fused saturated, partially saturated oraromatic (5- to 6-membered)-heterocyclyl is optionally substituted withone to twosubstituents per ring;

wherein said substituents are independently selected from the groupconsisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl;

wherein each of said R⁶ (i) (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

Subgeneric embodiments of the present invention of the “A” (i.e. A1, A2,A3, A4, A5, and A6) and R⁶ (i.e. R⁶(a), R⁶(b), R⁶(c), R⁶ (d), R⁶(e),R⁶(f), R⁶(g), R⁶(h), R⁶(i)) groups of compounds are expresslycontemplated by the present invention. Such subgeneric embodimentswithin the A1 group of compounds include the A1 group in combinationwith each of the R⁶ groups (i.e. A1-R⁶(a), A1-R⁶(b), A1-R⁶(c), A1-R⁶(d),A1-R⁶(e), A1-R⁶(f), A1-R⁶(g), A1-R⁶(h) and A1-R⁶(i)). Such subgenericembodiments within the A2 group of compounds include the A2 group incombination with each of the R⁶ groups (i.e. A2-R⁶(a), A2-R⁶(b),A2-R⁶(c), A2-R⁶(d), A2-R⁶(e), A2-R⁶(f), A2-R⁶(g), A2-R⁶(i)). Suchsubgeneric embodiments within the A3 group of compounds include the A3group in combination with each of the R⁶ groups (i.e. A3-R⁶(a),A3-R⁶(b), A3-R⁶(c), A3-R⁶(d), A3-R⁶(e), A3-R⁶(f), A3-R⁶(g), A3-R⁶(h) andA3-R⁶(i)). Such subgeneric embodiments within the A4 group of compoundsinclude the A4 group in combination with each of the R⁶ groups (i.e.A4-R⁶(a), A4-R⁶(b), A4-R⁶(c), A4-R⁶(d), A4-R⁶(e), A4-R⁶(f), A4-R⁶(g),A4-R⁶(h) and A4-R⁶(i)). Such subgeneric embodiments within the A5 groupof compounds include the A5 group in combination with each of the R⁶groups (i.e. A5-R⁶(a), A5-R⁶(b), A5-R⁶(c), A5-R⁶(d), A5-R⁶(e), A5-R⁶(f),A5-R⁶(g), A5-R⁶(h) and A5-R⁶(i)). Such subgeneric embodiments within theA6 group of compounds include the A6 group in combination with each ofthe R⁶ groups (i.e. A6-R⁶(a), A6-R⁶(b), A6-R⁶(c), A6-R⁶(d), A6-R⁶(e),A6-R⁶(f), A6-R⁶(h) and A6-R⁶(i)).

Preferred compounds of formula I are those compounds wherein the “A”ring is optionally substituted pyridin-2-yl or pyridin-3-yl; morepreferably wherein m is 2.

Other compounds of this invention are those of the formula I wherein R⁵is hydrogen, halo(such as fluoro), hydroxy, mercapto, (C₁-C₆)alkyl,(C₁-C₆)alkoxy optionally substituted with one to three halogen atoms,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, cyano, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylcarbonyloxy, hydroxycarbonyl,(C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido, or(C₁-C₆)alkylthio;

wherein each of said R⁵ (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

Other preferred compounds of this invention are those of the formula Iwherein R⁵ is hydrogen.

Other compounds of this invention are those of the formula I wherein R⁴is (C₁-C₆)alkyl, more preferably methyl, optionally substituted by oneto three halo atoms, such as fluoro atoms.

Other preferred compounds of this invention are those of the formula Iwherein R⁴ is (C₁-C₆)alkyl, more preferably methyl.

Other compounds of this invention are those of the formula I wherein R³is (C₁-C₆)alkylthio (such as methylthio), (C₃-C₇)carbocyclylthio (suchas cyclohexylthio), C₆-C₁₀)arylthio, (C₂-C₉)heteroarylthio,(C₁-C₆)alkyl-S(═O), (C₆-C₁₀)aryl-S(═O), (C₂-C₉)heteroaryl-S(═O),(C₁-C₆)alkyl-SO₂—, (C₆-C₁₀)aryl-SO₂—, (C₂-C₉)heteroaryl-SO₂—,(C₁-C₆)alkyl-SO₂-amino, (C₃-C₇)carbocyclyl-SO₂-amino,(C₆-C₁₀)aryl-SO₂-amino, (C₂-C₉)heteroaryl-SO₂-amino, amino-SO₂—,N—(C₁-C₆)alkylamino-SO₂—, N,N—[(C₁-C₆)alkyl]₂amino-SO₂—,N—(C₃-C₇)carbocyclylamino-SO₂—, N—(C₆-C₁₀)arylamino-SO₂—,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino-SO₂—, N—(C₂-C₉)heteroarylamino-SO₂—,amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, or N—(C₂-C₉)heteroarylamino;

wherein each of said (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.

Other preferred compounds of this invention are those of the formula Iwherein R³ is (C₁-C₆)alkylthio (such as methylthio),(C₃-C₇)carbocyclylthio (such as cyclohexylthio), C₈-C₁₀)arylthio,(C₂-C₉)heteroarylthio, (C₁-C₆)alkyl-S(═O), (C₆-C₁₀)aryl-S(═O),(C₂-C₉)heteroaryl-S(═O), (C₁-C₆)alkyl-SO₂—, (C₆-C₁₀)aryl-SO₂—,(C₂-C₉)heteroaryl-SO₂—, (C₁-C₆)alkyl-SO₂-amino,(C₃-C₇)carbocyclyl-SO₂-amino, (C₆-C₁₀)aryl-SO₂-amino,(C₂-C₉)heteroaryl-SO₂-amino, amino-SO₂—, N—(C₁-C₆)alkylamino-SO₂—,N,N—[(C₁-C₆)alkyl]₂amino-SO₂—, N—(C₃-C₇)carbocyclylamino-SO₂—,N—(C₆-C₁₀)arylamino-SO₂—, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino-SO₂—,N—(C₂-C₉)heteroarylamino-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, or N—(C₂-C₉)heteroarylamino.

Other preferred compounds of this invention are those of the formula Iwherein R³ is C₁-C₆)alkylthio (such as methylthio),(C₃-C₇)carbocyclylthio(such as cyclohexylthio), (C₆-C₁₀)arylthio,(C₂-C₉)heteroarylthio, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, orN—(C₂-C₉)heteroarylamino.

Other preferred compounds of this invention are those of the formula Iwherein R³ is (C₁-C₆)alkylthio, more preferably methylthio, wherein eachof said (C₁-C₈)alkyl group may optionally be substituted with one tothree substituents independently selected from hydroxycarbonyl or(C₁-C₆)alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl.

Other preferred compounds of this invention are those of the formula Iwherein R³ is (C₁-C₆)alkylthio (more preferably methylthio), amino,alkylsulfonylamino, sulfamylamino, alkylamino and alkylcarbonylamino;more preferably wherein R³ is (C₁-C₆)alkylthio or amino.

Other compounds of this invention are those of the formula I wherein R²is hydrogen, or (C₁-C₆)alkyl, such as methyl.

Other compounds of this invention are those of the formula I wherein R¹is hydrogen, cyano, halo, (C₁-C₆)alkyl (such as methyl) optionallysubstituted with one to three halo (such as fluoro) atoms,(C₁-C₆)alkylcarbonyl, or formyl.

Other preferred compounds of this invention are those of the formula Iwherein R¹ is hydrogen, halo, cyano, or (C₁-C₆)alkylcarbonyl, such asmethylcarbonyl.

Most preferred compounds of this invention are those of the formula Iwherein R¹ is cyano.

Other most preferred compounds of this invention are those of theformula I wherein the “A” ring is optionally substituted pyridin-2-yl orpyridin-3-yl; more preferably wherein m is 2; R¹ is cyano; R³ ismethylthio; R⁴ is methyl; R⁵ is hydrogen; and R⁶ is phenyl optionallysubstituted by one to three, preferably one, substituents independentlyselected from the group consisting of halo, most preferably chloro, or(C₁-C₆)alkyl, most preferably methyl.

Other most preferred compounds of this invention are those of theformula I wherein the “A” ring is optionally substituted pyridin-2-yl orpyridin-3-yl; more preferably wherein m is 2; R¹ is cyano; R³ ismethylthio; R⁴ is methyl; R⁵ is hydrogen; and R⁶ is phenyl optionallysubstituted with one to three, preferably one, halo, preferably chloro,or one to three, preferably one, (C₁-C₆)alkyl, preferably methyl.

Other most preferred compounds of this invention are those of theformula I wherein the “A” ring is optionally substituted pyridin-2-yl orpyridin-3-yl; more preferably wherein m is 2; R¹ is cyano; R³ ismethylthio; R⁴ is methyl; R⁵ is hydrogen; and R⁶ is unsubstitutedphenyl.

Other most preferred compounds of this invention are those of theformula I wherein the “A” ring is optionally substituted pyridin-2-yl orpyridin-3-yl; more preferably wherein m is 2; R¹ is cyano; R³ ismethylthio; R⁴ is methyl; R⁵ is hydrogen; and R⁶ is unsubstitutedaromatic (5- to 6-membered)-, more preferably (5-membered)-heterocyclyl,such as thienyl, most preferably 2-thienyl, or furanyl, most preferably2-furanyl.

Examples of specific preferred compounds of the formula I are thefollowing:

-   1-(5-Methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-5-phenyl-1H-pyrazole-4-carbonitrile;-   5-(4-Chloro-phenyl)-1-(5-methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-1H-pyrazole-4-carbonitrile;-   1-(5-Methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-5-p-tolyl-1H-pyrazole-4-carbonitrile;-   1-(5-Methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-5-thiophen-2-yl-1H-pyrazole-4-carbonitrile;-   1-(5-Methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-5-m-tolyl-1H-pyrazole-4-carbonitrile;-   5-(3-Chloro-phenyl)-1-(5-methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-1H-pyrazole-4-carbonitrile;-   3-Methanesulfonyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazole-4-carbonitrile;-   3-Azido-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazole-4-carbonitrile;-   3-Amino-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazole-4-carbonitrile;-   N-[4-Cyano-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazol-3-yl]-methanesulfonamide;-   [4-Cyano-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazol-3-ylamino]-acetic    acid;-   [4-Cyano-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazol-3-ylamino]-acetic    acid methyl ester;-   1-(6-Methanesulfonyl-pyridin-3-yl)-3-methylsulfanyl-5-phenyl-1H-pyrazole-4-carbonitrile;-   3-Methanesulfonyl-1-(6-methanesulfonyl-pyridin-3-yl)-5-phenyl-1H-pyrazole-4-carbonitrile;-   3-Methanesulfonyl-1-(6-methanesulfonyl-pyridin-3-yl)-5-phenyl-1H-pyrazole-4-carbonitrile;    and the pharmaceutically acceptable salts thereof.

The present invention also relates to a pharmaceutical composition forthe treatment of a condition selected from the group consisting ofarthritis (including osteoarthritis, degenerative joint disease,spondyloarthropathies, gouty arthritis, systemic lupus erythematosus,juvenile arthritis and rheumatoid arthritis), fever (including rheumaticfever and fever associated with influenza and other viral infections),common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease,Crohn's disease, emphysema, acute respiratory distress syndrome, asthma,bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease,organ transplant toxicity, cachexia, allergic reactions, allergiccontact hypersensitivity, cancer (such as solid tumor cancer includingcolon cancer, breast cancer, lung cancer and prostrate cancer;hematopoietic malignancies including leukemias and lymphomas; Hodgkin'sdisease; aplastic anemia, skin cancer and familiar adenomatouspolyposis), tissue ulceration, peptic ulcers, gastritis, regionalenteritis, ulcerative colitis, diverticulitis, recurrentgastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia,synovitis, gout, ankylosing spondylitis, restenosis, periodontaldisease, epidermolysis bullosa, osteoporosis, loosening of artificialjoint implants, atherosclerosis (including atherosclerotic plaquerupture), aortic aneurysm (including abdominal aortic aneurysm and brainaortic aneurysm), periarteritis nodosa, congestive heart failure,myocardial infarction, stroke, cerebral ischemia, head trauma, spinalcord injury, neuralgia, neuro-degenerative disorders (acute andchronic), autoimmune disorders, Huntington's disease, Parkinson'sdisease, migraine, depression, peripheral neuropathy, pain (includinglow back and neck pain, headache and toothache), gingivitis, cerebralamyloid angiopathy, nootropic or cognition enhancement, amyotrophiclateral sclerosis, multiple sclerosis, ocular angiogenesis, cornealinjury, macular degeneration, conjunctivitis, abnormal wound healing,muscle or joint sprains or strains, tendonitis, skin disorders (such aspsoriasis, eczema, scleroderma and dermatitis), myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes (including types I andII diabetes, diabetic retinopathy, neuropathy and nephropathy), tumorinvasion, tumor growth, tumor metastasis, corneal scarring, scleritis,immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats),sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis,sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease,Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoandiseases (such as malaria, giardia, coccidia), reproductive disorders(preferably in livestock), and septic shock in a mammal, preferably ahuman, cat livestock or a dog, comprising an amount of a compound offormula I or a pharmaceutically acceptable salt thereof effective insuch treatment and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition forthe treatment of a condition that can be treated by selectivelyinhibiting COX-2 in a mammal, preferably a human, cat, livestock or dog,comprising a COX-2 selective inhibiting effective amount of a compoundof formula I or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition forthe treatment of a condition selected from the group consisting ofinflammatory diseases such as arthritis (including osteoarthritis,degenerative joint disease, spondyloarthropathies, gouty arthritis,systemic lupus erythematosus, juvenile arthritis and rheumatoidarthritis), or fever (including rheumatic fever and fever associatedwith influenza).

The present invention also relates to a method for treating a conditionselected from the group consisting of arthritis (includingosteoarthritis, degenerative joint disease, spondyloarthropathies, goutyarthritis, systemic lupus erythematosus, juvenile arthritis andrheumatoid arthritis), fever (including rheumatic fever and feverassociated with influenza and other viral infections), common cold,dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn'sdisease, emphysema, acute respiratory distress syndrome, asthma,bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease,organ transplant toxicity, cachexia, allergic reactions, allergiccontact hypersensitivity, cancer (such as solid tumor cancer includingcolon cancer, breast cancer, lung cancer and prostrate cancer;hematopoietic malignancies including leukemias and lymphomas; Hodgkin'sdisease; aplastic anemia, skin cancer and familiar adenomatouspolyposis), tissue ulceration, peptic ulcers, gastritis, regionalenteritis, ulcerative colitis, diverticulitis, recurrentgastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia,synovitis, gout, ankylosing spondylitis, restenosis, periodontaldisease, epidermolysis bullosa, osteoporosis, loosening of artificialjoint implants, atherosclerosis (including atherosclerotic plaquerupture), aortic aneurysm (including abdominal aortic aneurysm and brainaortic aneurysm), periarteritis nodosa, congestive heart failure,myocardial infarction, stroke, cerebral ischemia, head trauma, spinalcord injury, neuralgia, neuro-degenerative disorders (acute andchronic), autoimmune disorders, Huntington's disease, Parkinson'sdisease, migraine, depression, peripheral neuropathy, pain (includinglow back and neck pain, headache and toothache), gingivitis, cerebralamyloid angiopathy, nootropic or cognition enhancement, amyotrophiclateral sclerosis, multiple sclerosis, ocular angiogenesis, cornealinjury, macular degeneration, conjunctivitis, abnormal wound healing,muscle or joint sprains or strains, tendonitis, skin disorders (such aspsoriasis, eczema, scleroderma and dermatitis), myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes (including types I andII diabetes, diabetic retinopathy, neuropathy and nephropathy), tumorinvasion, tumor growth, tumor metastasis, corneal scarring, scleritis,immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats),sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis,sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease,Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoandiseases (such as malaria, giardia, coccidia), reproductive disorders(preferably in livestock) and septic shock in a mammal, preferably ahuman, cat livestock or a dog, comprising administering to said mammalan amount of a compound of formula I or a pharmaceutically acceptablesalt thereof effective in treating such a condition.

The present invention also relates to a method for treating a disorderor condition that can be treated by selectively inhibiting COX-2 in amammal, preferably a human, cat livestock or a dog, comprisingadministering to a mammal requiring such treatment a COX-2 selectiveinhibiting effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

The present invention also relates to a method for treating a conditionselected from the group consisting of inflammatory diseases such asarthritis (including osteoarthritis, degenerative joint disease,spondyloarthropathies, gouty arthritis, systemic lupus erythematosus,juvenile arthritis and rheumatoid arthritis), or fever (includingrheumatic fever and fever associated with influenza).

This invention also relates to a method of or a pharmaceuticalcomposition for treating inflammatory processes and diseases comprisingadministering a compound of formula I of this invention or its salt to amammal including a human, cat, livestock or dog, wherein saidinflammatory processes and diseases are defined as above, and saidinhibitory compound is used in combination with one or more othertherapeutically active agents under the following conditions:

A.) where a joint has become seriously inflammed as well as infected atthe same time by bacteria, fungi, protozoa, and/or virus, saidinhibitory compound is administered in combination with one or moreantibiotic, antifungal, antiprotozoal, and/or antiviral therapeuticagents;

B.) where a multi-fold treatment of pain and inflammation is desired,said inhibitory compound is administered in combination with inhibitorsof other mediators of inflammation, comprising one or more membersindependently selected from the group consisting essentially of:

-   -   (1) NSAIDs;    -   (2) H₁-receptor antagonists;    -   (3) kinin-B₁- and B₂-receptor antagonists;    -   (4) prostaglandin inhibitors selected from the group consisting        of PGD-, PGF-PGI₂-, and PGE-receptor antagonists;    -   (5) thromboxane A₂ (TXA₂-) inhibitors;    -   (6) 5-, 12- and 15-lipoxygenase inhibitors;    -   (7) leukotriene LTC₄-, LTD₄/LTE₄-, and LTB₄-inhibitors;    -   (8) PAF-receptor antagonists;    -   (9) gold in the form of an aurothio group together with one or        more hydrophilic groups;    -   (10) immunosuppressive agents selected from the group consisting        of cyclosporine, azathioprine, and methotrexate;    -   (11) anti-inflammatory glucocorticoids;    -   (12) penicillamine;    -   (13) hydroxychloroquine;    -   (14) anti-gout agents including colchicine; xanthine oxidase        inhibitors including allopurinol; and uricosuric agents selected        from probenecid, sulfinpyrazone, and benzbromarone;

C.) where older mammals are being treated for disease conditions,syndromes and symptoms found in geriatric mammals, said inhibitorycompound is administered in combination with one or more membersindependently selected from the group consisting essentially of:

-   -   (1) cognitive therapeutics to counteract memory loss and        impairment;    -   (2) anti-hypertensives and other cardiovascular drugs intended        to offset the consequences of atherosclerosis, hypertension,        myocardial ischemia, angina, congestive heart failure, and        myocardial infarction, selected from the group consisting of:        -   a. diuretics;        -   b. vasodilators;        -   c. β-adrenergic receptor antagonists;        -   d. angiotensin-II converting enzyme inhibitors            (ACE-inhibitors), alone or optionally together with neutral            endopeptidase inhibitors;        -   e. angiotensin II receptor antagonists;        -   f. renin inhibitors;        -   g. calcium channel blockers;        -   h. sympatholytic agents;        -   i. α₂-adrenergic agonists;        -   j. α-adrenergic receptor antagonists; and        -   k. HMG-CoA-reductase inhibitors            (anti-hypercholesterolemics);    -   (3) antineoplastic agents selected from:        -   a. antimitotic drugs selected from:            -   i. vinca alkaloids selected from:                -   [1] vinblastine, and                -   [2] vincristine;    -   (4) growth hormone secretagogues;    -   (5) strong analgesics;    -   (6) local and systemic anesthetics; and    -   (7) H₂-receptor antagonists, proton pump inhibitors, and other        gastroprotective agents.

The term “treating”, as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or one or more symptoms of such disorder orcondition. The term “treatment”, as used herein, refers to the act oftreating, as “treating” is defined immediately above.

The term “livestock animals” as used herein refers to domesticatedquadrupeds, which includes those being raised for meat and variousbyproducts, e.g., a bovine animal including cattle and other members ofthe genus Bos, a porcine animal including domestic swine and othermembers of the genus Sus, an ovine animal including sheep and othermembers of the genus Ovis, domestic goats and other members of the genusCapra; domesticated quadrupeds being raised for specialized tasks suchas use as a beast of burden, e.g., an equine animal including domestichorses and other members of the family Equidae, genus Equus, or forsearching and sentinel duty, e.g., a canine animal including domesticdogs and other members of the genus Canis; and domesticated quadrupedsbeing raised primarily for recreational purposes, e.g., members of Equusand Canis, as well as a feline animal including domestic cats and othermembers of the family Felidae, genus Felis.

“Companion animals” as used herein refers to cats, dogs and horses. Asused herein, the term “dog(s)” denotes any member of the species Canisfamiliaris , of which there are a large number of different breeds.While laboratory determinations of biological activity may have beencarried out using a particular breed, it is contemplated that theinhibitory compounds of the present invention will be found to be usefulfor treating pain and inflammation in any of these numerous breeds. Dogsrepresent a particularly preferred class of patients in that they arewell known as being very susceptible to chronic inflammatory processessuch as osteoarthritis and degenerative joint disease, which in dogsoften results from a variety of developmental diseases, e.g., hipdysplasia and osteochondrosis, as well as from traumatic injuries tojoints. Conventional NSAIDs, if used in canine therapy, have thepotential for serious adverse gastrointestinal reactions and otheradverse reactions including kidney and liver toxicity. Gastrointestinaleffects such as single or multiple ulcerations, including perforationand hemorrhage of the esophagus, stomach, duodenum or small and largeintestine, are usually debilitating, but can often be severe or evenfatal.

The term “treating reproductive disorders (preferably in livestock)” asused herein refers to the use of the COX-2 inhibitors of the inventionin mammals, preferably livestock animals (cattle, pigs, sheep, goats orhorses), during the estrus cycle to control the time of onset of estrusby blocking the uterine signal for lysis of the corpus luteum, i.e.F-series prostaglandins, then removing the inhibition when the onset ofestrus is desired. There are settings where it is useful to control orsynchronize the time of estrus, especially when artificial inseminationor embryo transfer are to be performed. Such use also includes enhancingthe rate of embryo survival in pregnant livestock animals. BlockingF-series prostaglandin release can have several beneficial actionsincluding reducing uterine contractions, enhancing uteroplacentalbloodflow, supporting recognition of pregnancy, and postponing lysis ofthe corpus luteum at the time when estrus would have occurred had theanimal not become pregnant (around Day 21 of pregnancy). Such treatmentalso abrogates the effects of stress on reproduction. For examplereductions in fertility caused by excessive heat, negative energybalance and other stresses which have a COX-2 mediated component, asdoes abortion induced by stress such as heat, transportation,co-mingling, palpation, infection, etc. Such treatment is also useful tocontrol the time of parturition, which is accompanied by release ofF-series prostaglandins that lead to lysis of the corpus luteum.Inhibition of COX-2 would block the onset of premature labor inlivestock animals, allowing the offspring time to mature before birth.Also there are settings where controlling the time of parturition is auseful tool for management of pregnant animals.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in Formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine,. such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labelled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, ie., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of Formula I of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

This invention also encompasses pharmaceutical compositions containingprodrugs of compounds of the formula I. This invention also encompassesmethods of treating disorders that can be treated by the selectiveinhibition of COX-2 comprising administering prodrugs of compounds ofthe formula I. Compounds of formula I having free amino, amido, hydroxy,carboxylic acid ester, sulfonamide or carboxylic groups (especiallyalkyl-S— and alkyl-(S═O)—) can be converted into prodrugs. Prodrugsinclude compounds wherein an amino acid residue, or a polypeptide chainof two or more (e.g., two, three or four) amino acid residues which arecovalently joined through peptide bonds to free amino, hydroxy orcarboxylic acid groups of compounds of formula I. The amino acidresidues include the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also include, 4-hydroxyproline,hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin,beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine,homoserine, ornithine and methionine sulfone. Prodrugs also includecompounds wherein carbonates, carbamates, amides and alkyl esters arecovalently bonded to the above substituents of formula I through thecarbonyl carbon prodrug sidechain. Prodrugs also include metabolicallylabile groups such as ethers, acetates, mercaptans and sulfoxides.

One of ordinary skill in the art will appreciate that the compounds ofthe invention are useful in treating a diverse array of diseases. One ofordinary skill in the art will also appreciate that when using thecompounds of the invention in the treatment of a specific disease thatthe compounds of the invention may be combined with various existingtherapeutic agents used for that disease.

For the treatment of rheumatoid arthritis, the compounds of theinvention may be combined with agents such as TNF-α inhibitors such asanti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules(such as Enbrel®), low dose methotrexate, lefunimide,hydroxychloroquine, d-penicilamine, auranofin or parenteral or oralgold.

The compounds of the invention can also be used in combination withexisting therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as celecoxib androfecoxib, analgesics and intraarticular therapies such ascorticosteroids and hyaluronic acids such as hyalgan and synvisc.

The active ingredient of the present invention may be administered incombination with inhibitors of other mediators of inflammation,comprising one or more members selected from the group consistingessentially of the classes of such inhibitors and examples thereof whichinclude, matrix metalloproteinase inhibitors, aggrecanase inhibitors,TACE inhibitors, leucotriene receptor antagonists, IL-1 processing andrelease inhibitors, ILra, H₁-receptor antagonists; kinin-B₁- andB₂-receptor antagonists; prostaglandin inhibitors such as PGD-,PGF-PGI₂-, and PGE-receptor antagonists; thromboxane A₂ (TXA2-)inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene LTC₄-,LTD₄/LTE₄-, and LTB₄-inhibitors; PAF-receptor antagonists; gold in theform of an aurothio group together with various hydrophilic groups;immunosuppressive agents, e.g., cyclosporine, azathioprine, andmethotrexate; anti-inflammatory glucocorticoids; penicillamine;hydroxychloroquine; anti-gout agents, e.g., coichicine, xanthine oxidaseinhibitors, e.g., allopurinol, and uricosuric agents, e.g., probenecid,sulfinpyrazone, and benzbromarone.

The compounds of the present invention may also be used in combinationwith anticancer agents such as endostatin and angiostatin or cytotoxicdrugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol,taxotere and alkaloids, such as vincristine, and antimetabolites such asmethotrexate.

The compounds of the present invention may also be used in combinationwith anti-hypertensives and other cardiovascular drugs intended tooffset the consequences of atherosclerosis, including hypertension,myocardial ischemia including angina, congestive heart failure, andmyocardial infarction, selected from vasodilators such as hydralazine,β-adrenergic receptor antagonists such as propranolol, calcium channelblockers such as nifedipine, α₂-adrenergic agonists such as clonidine,α-adrenergic receptor antagonists such as prazosin, andHMG-CoA-reductase inhibitors (anti-hypercholesterolemics) such aslovastatin or atorvastatin.

The active ingredient of the present invention may also be administeredin combination with one or more antibiotic, antifungal, antiprotozoal,antiviral or similar therapeutic agents.

The compounds of the present invention may also be used in combinationwith CNS agents such as antidepressants (such as sertraline),anti-Parkinsonian drugs (such as L-dopa, requip, mirapex, MAOBinhibitors such as selegine and rasagiline, comP inhibitors such asTasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,nicotine agonists, dopamine agonists and inhibitors of neuronal nitricoxide synthase), and anti-Alzheimer's drugs such as donepezil, tacrine,COX-2 inhibitors, propentofylline or metryfonate.

The compounds of the present invention may also be used in combinationwith osteoporosis agents such as roloxifene, lasofoxifene, droloxifeneor fosomax and immunosuppressant agents such as FK-506 and rapamycin.

The present invention also relates to the formulation of the activeagents of the present invention alone or with one or more othertherapeutic agents which are to form the intended combination, includingwherein said different drugs have varying half-lives, by creatingcontrolled-release forms of said drugs with different release timeswhich achieves relatively uniform dosing; or, in the case of non-humanpatients, a medicated feed dosage form in which said drugs used in thecombination are present together in admixture in said feed composition.There is further provided in accordance with the present inventionco-administration in which the combination of drugs is achieved by thesimultaneous administration of said drugs to be given in combination;including co-administration by means of different dosage forms androutes of administration; the use of combinations in accordance withdifferent but regular and continuous dosing schedules whereby desiredplasma levels of said drugs involved are maintained in the patient beingtreated, even though the individual drugs making up said combination arenot being administered to said patient simultaneously.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated, R¹through R⁷, A, X and m in the reaction schemes and discussion thatfollow are as defined above.

Scheme 1 illustrates methods of synthesizing compounds of the formula I.Referring to Scheme 1, a compound of the formula I,

wherein the heterocyclic

has a general formula

wherein each of X, Y, or Z can independently be CR⁷ or N and at leastone of X, Y, or Z must be N (ie., compounds of general formulae A1(wherein X is CR⁷or N, Y is CH, and Z is N), A2 (wherein X is CR⁷ or N,Y is CH, and Z is N), A3 (wherein X is CH, Y is N, and Z is N), A4(wherein X is N, Y is N, and Z is N), A5 (wherein X is N, Y is N, and Zis N), and A6 (wherein X is N, Y is N, and Z is CH)). Specifically, thecompounds of formula I (ie., a compound of the formulae IA1-IA6,respectively):

can be prepared by reacting a compound of formula II, wherein L¹ is aleaving group, with a a compound of formula M-R³, wherein M is a cationsuch as sodium, in a solvent. In the aforesaid reaction, said L¹ isdisplaced with said R³. Suitable leaving group L¹ includes halo, such asbromo or chloro, or (C₁-C₆)alkylsulfonate, such as methylsulfonate. Theaforesaid reaction can be performed in neutral or basic conditions bymethods familiar to those in the art. Suitable solvents include alcohol(such as methanol or ethanol), di(C₁-C₆)alkylethers (such asdiethylether), halogenated solvents (such as methylene chloride), ordimethylformamide (DMF). This reaction can be carried out at atemperature of from about −20° C. to about 120° C., preferably fromabout 25° C. to about 50° C. This reaction can be carried out for aperiod of from about 1 hour to about 72 hours, preferably for about 24hours.

The compound of formula II, wherein L¹ is a leaving group including halo(compound IIa) or sulfonate (compound IIb) can be prepared by reacting acompound of formula III, with an appropriate reagent, optionally in thepresence of a solvent and a base. Suitable halo L¹ leaving groupsinclude bromo or chloro. Suitable sulfonate L¹ leaving groups include(C₁-C₆)alkylsulfonate (such as methylsulfonate),trihalo(C₁-C₆)alkylsulfonate (such as trifluoromethylsulfonate), or(C₆-C₁₀)arylsulfonate (such as para-toluenesulfonate). When L¹ is halo,a suitable appropriate reagent is phosphoryloxychloride orphosphoryloxybromide. When L¹ is a sulfonate, a suitable appropriatereagent is triflic anhydride, mesyl chloride or tosyl chloride. Suitablesolvents include methylene chloride, DMF or tetrahydrofuran (THF).Suitable bases include triethylamine, sodium hydride,potassiumcarbonate, or sodiumhydroxide. This reaction can be carried outat a temperature of from about 0° C. to about 100° C., preferably about80° C. in the preparation of the compound of formula IIa; or about 25°C. in the preparation of the compound of formula IIb. This reaction canbe carried out for a period of from about 1 hour to about 72 hours,preferably for about 24 hours.

The compound of formula III can be prepared by reacting a compound offormula IV with a compound of formula V:

or an acidic salt thereof, such as a hydrochloric salt thereof,

wherein the heterocyclic

as a general formula

wherein each of X, Y, or Z can be CR⁷ or N and at least one of X, Y, orZ must be N as defined above. Specifically, the compounds of formula V(i.e., a compound of the formulae VA1-VA6, respectively):

can be reacted with a compound of formula IV under acidic, neutral orbasic conditions, preferably in the presence of an acid or an acid saltof the compound of formula V in a solvent. Suitable acids includehydrochloric acid, acetic acid, trifluoroaceticacid,para-toluenesulfonic acid or sulfuric acid, preferably hydrochloricacid. Suitable acid salts include sodium acetate. Suitable bases includesodium hydroxide or potassium hydroxide. Suitable solvents includealcohol, such as ethanol, trifluoroethanol, methanol, propanol,isopropanol or butanol; dimethyl sulfoxide (DMSO), DMF,N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidinone (NMP), benzene,toluene, chloroform or mixtures thereof, preferably alcohol, mostpreferably ethanol or isopropanol. This reaction can be carried out at atemperature from about 0° C. to about 140° C., preferably at about 80°C. to about 100° C., or at reflux temperature of the solvent used. Thisreaction can be carried out for a period of from about 1 hour to about72 hours, preferably for about 24 hours.

The compound of formula IV can be purchased or can be prepared accordingto methods described in the literature, e.g., Advanced OrganicChemistry, 4^(th) ed.,1992; J. Med. Chem. 1997, 40, 1347-1365; andreferences cited therein.

Scheme 2 illustrates alternative methods of synthesizing compounds ofthe formula IIb, as defined above. Referring to Scheme 2, a compound ofthe formula IIb can be prepared by reacting a compound of formula VIwith an oxidizing agent in a solvent optionally in the presence of abase. Suitable oxidizing agents include meta-chloroperbenzoic acid,hydrogen peroxide, OXONE®, nitric acid or barium permangate. Suitablesolvents include alcohol-water (such as methanol-water orethanol-water), dioxane-water, tetrahydrofuran-water, methylenechloride, chloroform, di(C₁-C₆)alkylethers (such as diethylether),halogenated solvents (such as methylene chloride), or DMF, preferablymethanol-water. Suitable bases include sodium hydroxide. This reactioncan be carried out at a temperature of from about 0° C. to about 25° C.,preferably from about 20° C. to about 25° C. This reaction can becarried out for a period of from about 0.5 hours to about 24 hours,preferably for about 3 hours.

The compound of formula VI can be prepared by reacting a compound offormula VII with a compound of formula V (i.e., a compound of theformulae VA1-VA6, respectively, as defined above), or an acidic saltthereof, such as a hydrochloric salt thereof, under acidic, neutral orbasic conditions, preferably in the presence of an acid or an acid saltof the compound of the formula V in a solvent. Suitable acids includehydrochloric acid, acetic acid, trifluoroaceticacid,para-toluenesulfonic acid or sulfuric acid, preferably hydrochloricacid. Suitable acid salts include sodium acetate. Suitable bases includesodium hydroxide or potassium hydroxide. Suitable solvents includealcohol (such as ethanol, trifluoroethanol, methanol, propanol,isopropanol or butanol), alcohol-water, DMSO, DMF, DMA, NMP, benzene,toluene, chloroform or mixtures thereof, preferably alcohol, mostpreferably ethanol or isopropanol. This reaction can be carried out at atemperature from about 60° C. to about 100° C. This reaction can becarried out for a period of from about 1 hour to about 24 hours.

The compound of formula VII can be purchased or can be preparedaccording to methods described in the literature, e.g., Advanced OrganicChemistry, 4^(th) ed.,1992.

Scheme 3 refers to the preparation of compounds of the formula V (i.e.,a compound of the formulae VA1-VA6, respectively, as defined above) in amulti-step process from a compound of formula X, wherein each of L² andL³, individually, are leaving groups. Referring to Scheme 3, a compoundof the formula V can be prepared by reacting a compound of the formulaVIII (i.e., a compound of the formulae VIIIA1-VIIIA6, respectively):

wherein L³ is a leaving group, with hydrazine (preferably anhydroushydrazine) in the presence of a solvent. Suitable L³ leaving groupsinclude halo, preferably chloro or bromo. Suitable solvents includealcohol (such as ethanol, methanol, propanol or butanol), DMSO, DMF,DMA, or NMP, preferably alcohol, most preferably ethanol. This reactioncan be carried out at a temperature from about 0° C. to about 140° C.,preferably from about 80° C. to about 100° C., or at about the refluxtemperature of the solvent used in this reaction. This reaction can becarried out for a period of from about 1 hour to about 72 hours,preferably from about 1 hour to about 24 hours. Preferably the productis isolated as a salt, such as a hydrobromide or hydrochloride salt,preferably hydrochloride salt.

The compound of formula VIII (i.e., a compound of the formulaeVIIIA1-VIIIA6, respectively, as defined above) can be prepared byreacting a compound of the formula IX (i.e., a compound of the formulaeIXA1-IXA6, respectively):

wherein L³ is a leaving group, with an oxidizing reagent in the presenceof a solvent. Suitable leaving groups include halo, sulfonate, orsulfone, preferably halo such as chloro or bromo. Suitable oxidizingagents include meta-chloroperbenzoic acid, hydrogen peroxide, sodiumperborate, or OXONE® Suitable solvents or solvent mixtures includemethanol-water, dioxane-water, tetrahydrofuran-water, methylenechloride, or chloroform, preferably methanol-water. This reaction can becarried out at a temperature from about 0° C. to about 60° C.,preferably the temperature may range from about 20° C. to about 25° C.(i.e. room temperature). This reaction can be carried out for a periodof from about 0.5 hours to about 24 hours, preferably about 16 hours.

The compounds of the, formula IX (i.e., a compound of the formulaeIXA1-IXA6, respectively, as defined above) can be prepared by reacting acompound of formula X (i.e., a compound of the formulae XA1-XA6,respectively):

wherein each of L² and L³ independently is a leaving group, with asulfur nucleophilic reagent optionally in the presence of a base in asolvent. Suitable leaving groups L² include halo (such as chloro orbromo), sulfonate, or sulfone, preferably chloro or bromo. Suitableleaving groups L³ include halo (such as chloro or bromo), sulfonate, orsulfone, preferably chloro or bromo. Suitable sulfur nucleophilicreagents include alkylthiol, dialkyldisulfide, alkylsulfonate, sodiumthioalkoxide or potassium thioalkoxide. Suitable bases include sodiumhydroxide, triethylamine, alkyllithium (such as n-butyllithium,sec-butyllithium, or tert-butyllithium), or lithium diisopropylamide.Suitable solvents include di(C₁-C₆)alkylether (such as dimethylether),alcohol (such as methanol, ethanol or tert-butanol), THF, benzene,toluene, xylene, DMF, DMSO, dioxane, 1,2-dimethoxyethane, and a mixtureof alcohol and water. This reaction can be carried out at a temperaturefrom about −78° C. to about 200° C., preferably from about 0° C. toabout 100° C. This reaction can be carried out for a period of fromabout 1 minute to 1 day, preferably about 30 minutes.

Scheme 4 refers to an alternative preparation of compounds of theformula V (i.e., a compound of the formulae VA1-VA6, respectively, asdefined above) by multi step reactions, i.e., a nitrosation reactionfollowed by reduction. Referring to Scheme 4, a compound of the formulaV can be prepared by reacting a compound of formula XI (i.e., a compoundof the formulae XIA1-XIA6, respectively):

wherein P is —NH—NO or —N≡N⁺, with a reducing agent or a catalytichydrogenating agent in an inert solvent. Suitable reducing agentsinclude metal halides such as TiCl₃, SnCl₂, zinc powder-acetic acid,sodium-ethanol, sodium-aqueous ammonia, lithium aluminum hydride and thelike. Suitable catalytic hydrogenating agents include hydrogen gas at apressure from about 1 atmosphere to about 5 atmospheres and atemperature of from about 10° C. to about 60° C., in the presence of acatalyst such as palladium on carbon (Pd/C), palladium on barium sulfate(Pd/BaSO₄), platinum on carbon (Pt/C), or tris(triphenylphosphine)rhodium chloride (Wilkinson's catalyst). Preferably the catalytichydrogenating agent is Pd/C at 25° C. and 50 psi of hydrogen gaspressure in methanol solvent. Suitable solvents include alcohol (such asmethanol or ethanol), THF, dioxane, or ethyl acetate. This method alsoprovides for introduction of hydrogen isotopes (i.e., deuterium ortritium) by replacing ¹H₂ with ²H₂ or ³H₂ in the above procedure.

A compound of the formula XI (i.e., a compound of the formulaeXIA1-XIA6, respectively, as defined above) can be prepared by reactionof a compound of the formula XII (i.e., a compound of the formulaeXIIA1-XIIA6, respectively):

with a suitable reagent. Suitable reagents include sodium nitrite in anaqueous medium (such as hydrochloric acid in water), nitrosyl chloride,nitrogen oxides and nitrile ethers. This reaction can be carried out ata temperature from about −78° C. to about 200° C., preferably from about−10° C. to about 0° C. This reaction can be carried out for a period ofabout 1 minute to about 10 hours.

Compounds of formula XII (i.e., a compound of the formulae XIIA1-XIIA6,respectively, as defined above) are commercially available or can beprepared by methods well known to those of ordinary skill in the art(see F. Walker et al., J. Chem. Soc. 1939, 1948).

Compounds of the formula V (i.e., a compound of the formulae VA1-VA6,respectively, as defined above) may be prepared by methods well known tothose of ordinary skill in the art (see Collection Czechoslov. Chem.Commun. Vol. 37, p. 1721, 1972 by J. Vafrina et. al.; European PatentPublications EP 1104759 and EP 1104760).

Other methods of preparing the compounds of Formula I are well known tothose skilled in the art such as those described in Heterocycles,31,1041 (1990). The compounds of formula I can also be synthesized byusing the method of Kharash, Negishi, Stille, or Suzuki et. al., whichare well known in the art. In general, heteroaryl compounds aresynthesized by a number of catalytic cross-coupling reactions fromheteroaryl halides or triflates and heteroaryl metal reagents (such asGrignard reagent (the so-called Kharasch reaction), heteroaryl zincreagent (the so-called Negishi reaction), heteroaryl tin reagent (theso-called Stille reaction), heteroaryl silyl reagent, etc. (see forexample S. P. Stanforth, Tetrahedron, 1998, 54, 263-303)).

Unless indicated otherwise, the pressure of each of the above reactionsis not critical. Generally, the reactions will be conducted at apressure of about one to about three atmospheres, preferably at ambientpressure (about one atmosphere).

Those skilled in the art will appreciate that the above schemes describegeneral methods for preparing the compounds of the invention. Specificcompounds of formula I may possess sensitive functional groups thatrequire protecting groups when prepared with the intermediatesdescribed. Examples of suitable protecting groups may be found in T. W.Greene and P. Wuts, Protecting Groups in Organic Synthesis, John Wiley &Sons, 2nd Edition, New York, 1991.

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula I which are also acidic in nature, e.g.,wherein A or any of R¹, R³, R⁴, R⁵or R⁶ include a hydroxycarbonyl,tetrazole, or other acidic moiety, are capable of forming base saltswith various pharmacologically acceptable cations. Examples of suchsalts include the alkali metal or alkaline-earth metal salts andparticularly, the sodium and potassium salts. These salts are allprepared by conventional techniques. The chemical bases which are usedas reagents to prepare the pharmaceutically acceptable base salts ofthis invention are those which form non-toxic base salts with the hereindescribed acidic compounds of formula I. These non-toxic base saltsinclude those derived from such pharmacologically acceptable cations assodium, potassium, calcium and magnesium, etc. These salts can easily beprepared by treating the corresponding acidic compounds with an aqueoussolution containing the desired pharmacologically acceptable cations,and then evaporating the resulting solution to dryness, preferably underreduced pressure. Alternatively, they may also be prepared by mixinglower alkanolic solutions of the acidic compounds and the desired alkalimetal alkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensurecompleteness of reaction and maximum product yields.

Method for Assessing Biological Activities

The activity of the compounds of the formula I of the present inventionwas demonstrated by the following assays.

Human In Vitro Assays

Human Cell-Based COX-1 Assay

Human peripheral blood obtained from healthy volunteers was diluted to1/10 volume with 3.8% sodium citrate solution. The platelet-rich plasmaimmediately obtained was washed with 0.14 M sodium chloride containing12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA. Platelets were then washed withplatelet buffer (Hanks buffer (Ca free) containing 0.2% BSA and 20 mMHepes). Finally, the human washed platelets (HWP) were suspended inplatelet buffer at the concentration of 2.85×10⁸ cells/ml and stored atroom temperature until use. The HWP suspension (70 μl aliquots, final2.0×10⁷ cells/ml) was placed in a 96-well U bottom plate and 10 μlaliquots of 12.6 mM calcium chloride added. Platelets were incubatedwith A23187 (final 10 μM, Sigma) with test compound (0.1-100 μM)dissolved in DMSO (final concentration; less than 0.01%) at 37° C. for15 minutes. The reaction was stopped by addition of EDTA (final 7.7 mM)and TxB2 in the supernatant quantitated by using a radioimmunoassay kit(Amersham) according to the manufacturer's procedure.

Human Cell-Based COX-2 Assay

The human cell based COX-2 assay was carried out as previously described(Moore et al., Inflam. Res., 45, 54, 1996). Confluent human umbilicalvein endothelial cells (HUVECs, Morinaga) in a 96-well flat bottom platewere washed with 80 ml of RPMI1640 containing 2% FBS and incubated withhIL-1β (final concentration 300 U/ml, R & D Systems) at 37° C. for 24hours. After washing, the activated HUVECs were incubateed with testcompound (final concentration; 0.1 nM-1 μM) dissolved in DMSO (finalconcentration; less than 0.01%) at 37° C. for 20 minutes and stimulatedwith A23187 (final concentration 30 mM) in Hanks buffer containing 0.2%BSA, 20 mM Hepes at 37° C. for 15 minutes. 6-Keto-PGF_(1α), stablemetabolite of PGI2, in the supernatant was quantitated by using aradioimmunoassay method (antibody; Preseptive Diagnostics, SPA;Amersham).

Canine In Vitro Assays

The following canine cell based COX 1 and COX-2 assays have beenreported in Ricketts et al., Evaluation of Selective Inhibition ofCanine Cyclooxyenase 1 and 2 by Carprofen and Other NonsteroidalAnti-inflammatory Drugs, American Journal of Veterinary Research, 59(11), 1441-1446.

Protocol for Evaluation of Canine COX-1 Activity

Test drug compounds were solubilized and diluted the day before theassay was to be conducted with 0.1 mL of DMSO/9.9 mL of Hank's balancedsalts solution (HBSS), and stored overnight at 4° C. On the day that theassay was carried out, citrated blood was drawn from a donor dog,centrifuged at 190×g for 25 minutes at room temperature, and theresulting platelet-rich plasma was then transferred to a new tube forfurther procedures. The platelets were washed by centrifuging at 1500×gfor 10 minutes at room temperature. The platelets were washed withplatelet buffer comprising Hank's buffer (Ca free) with 0.2% bovineserum albumin (BSA) and 20 mM HEPES. The platelet samples were thenadjusted to 1.5×10⁷/mL, after which 50 μl of calcium ionophore (A23187)together with a calcium chloride solution were added to 50 μl of testdrug compound dilution in plates to produce final concentrations of 1.7μM A23187 and 1.26 mM Ca. Then, 100 μl of canine washed platelets wereadded and the samples were incubated at 37° C. for 15 minutes, afterwhich the reaction was stopped by adding 20 μl of 77 mM EDTA. The plateswere then centrifuged at 2000×g for 10 minutes at 4° C., after which 50μof supernatant was assayed for thromboxane B₂ (TXB₂) byenzyme-immunoassay (EIA). The pg/mL of TXB₂ was calculated from thestandard line included on each plate, from which it was possible tocalculate the percent inhibition of COX-1 and the IC₅₀ values for thetest drug compounds.

Protocol for Evaluation of Canine COX-2 Activity

A canine histocytoma (macrophage-like) cell line from the American TypeCulture Collection designated as DH82, was used in setting up theprotocol for evaluating the COX-2 inhibition activity of various testdrug compounds. There was added to flasks of these cells 10 μg/mL ofLPS, after which the flask cultures were incubated overnight. The sametest drug compound dilutions as described above for the COX-1 protocolwere used for the COX-2 assay and were prepared the day before the assaywas carried out. The cells were harvested from the culture flasks byscraping, and were then washed with minimal Eagle's media (MEM) combinedwith 1% fetal bovine serum, centrifuged at 1500 rpm for 2 minutes, andadjusted to a concentration of 3.2×10⁵ cells/mL. To 50 μl of test drugdilution there was added 50 μl of arachidonic acid in MEM to give a 10μM final concentration, and there was added as well 100 μl of cellsuspension to give a final concentration of 1.6×10⁵ cells/mL. The testsample suspensions were incubated for 1 hour and then centrifuged at1000 rpm for 10 minutes at 4° C., after which 50 μl aliquots of eachtest drug sample were delivered to EIA plates. The EIA was performed forprostaglandin E₂ (PGE₂), and the pg/mL concentration of PGE₂ wascalculated from the standard line included on each plate. From this datait was possible to calculate the percent inhibition of COX-2 and theIC₅₀ values for the test drug compounds. Repeated investigations ofCOX-1 and COX-2 inhibition were conducted over the course of severalmonths. The results are averaged, and a single COX-1: COX-2 ratio iscalculated.

Whole blood assays for COX-1 and COX-2 are known in the art such as themethods described in C. Brideau, et al., A Human Whole Blood Assay forClinical Evaluation of Biochemical Efficacy of CyclooxygenaseInhibitors, Inflammation Research, Vol. 45, pp. 68-74 (1996). Thesemethods may be applied with feline, canine or human blood as needed.

In Vivo Assays

Carrageenan Induced Foot Edema in Rats

Male Sprague-Dawley rats (5 weeks old, Charles River Japan) were fastedovernight. A line was drawn using a marker above the ankle on the righthind paw and the paw volume (VO) was measured by water displacementusing a plethysmometer (Muromachi). Animals were given orally eithervehicle (0.1% methyl cellulose or 5% Tween 80) or a test compound (2.5ml per 100 g body weight). One hour later, the animals were theninjected intradermally with λ-carrageenan (0.1 ml of 1% w/v suspensionin saline, Zushikagaku) into right hind paw (Winter et al., Proc. Soc.Exp. Biol. Med., 111, 544, 1962; Lombardino et al., Arzneim. Forsch.,25, 1629, 1975) and three hours later, the paw volume (V3) was measuredand the increase in volume (V3-V0) calculated. Since maximum inhibitionattainable with classical NSAIDs is 60-70%, ED₃₀ values were calculated.

Gastric Ulceration in Rats

The gastric ulcerogenicity of test compound was assessed by amodification of the conventional method (Ezer et al., J. Pharm.Pharmacol., 28, 655, 1976; Cashin et al., J. Pharm. Pharmacol., 29,330-336, 1977). Male Sprague-Dawley rats (5 weeks old, Charles RiverJapan), fasted overnight, were given orally either vehicle (0.1% methylcellulose or 5% Tween 80) or a test compound (1 ml per 100 g bodyweight). Six hours after, the animals were sacrificed by cervicaldislocation. The stomachs were removed and inflated with 1% formalinsolution (10 ml). Stomachs were opened by cutting along the greatercurvature. From the number of rats that showed at least one gastriculcer or haemorrhaging erosion (including ecchymosis), the incidence ofulceration was calculated. Animals did not have access to either food orwater during the experiment.

Canine Whole Blood ex vivo Determinations of COX-1 and COX-2 ActivityInhibition

The in vivo inhibitory potency of a test compound against COX-1 andCOX-2 activity may be evaluated using an ex vivo procedure on caninewhole blood. Three dogs were dosed with 5 mg/kg of the test compoundadministered by oral gavage in 0.5% methylcellulose vehicle and threedogs were untreated. A zero-hour blood sample was collected from alldogs in the study prior to dosing, followed by 2- and 8-hour post-doseblood sample collections. Test tubes were prepared containing 2 μL ofeither (A) calcium ionophore A23187 giving a 50 μM final concentration,which stimulates the production of thromboxane B₂ (TXB₂) for COX-1activity determination; or of (B) lipopolysaccharide (LPS) to give a 10μ/mL final concentration, which stimulates the production ofprostaglandin E₂ (PGE₂) for COX-2 activity determination. Test tubeswith unstimulated vehicle were used as controls. A 500 μL sample ofblood was added to each of the above-described test tubes, after whichthey were incubated at 37° C. for one hour in the case of the calciumionophore-containing test tubes, and overnight in the case of theLPS-containing test tubes. After incubation, 10 μL of EDTA was added togive a final concentration of 0.3%, in order to prevent coagulation ofthe plasma which sometimes occurs after thawing frozen plasma samples.The incubated samples were centrifuged at 4° C. and the resulting plasmasample of ˜200 μL was collected and stored at −20° C. in polypropylene96-well plates. In order to determine endpoints for this study, enzymeimmunoassay (EIA) kits available from Cayman were used to measureproduction of TXB₂ and PGE₂, utilizing the principle of competitivebinding of tracer to antibody and endpoint determination by colorimetry.Plasma samples were diluted to approximate the range of standard amountswhich would be supplied in a diagnostic or research tools kit, i.e.,1/500 for TXB₂ and 1/750 for PGE₂.

The data set out in Table 1 below show how the percent inhibition ofCOX-1 and COX-2 activity is calculated based on their zero hour values.The data is expressed as treatment group averages in pg/ml of TXB₂ andPGE₂ produced per sample. Plasma dilution was not factored in said datavalues.

The data in Table 1 show that, in this illustration, at the 5 mg/kg dosethere was significant COX-2 inhibition at both timepoints. The data inTable 1 also show that at the 5 mg/kg dose there was no significantinhibition of COX-1 activity at the timepoints involved. Accordingly,the data in Table 1 clearly demonstrates that at the 5 mg/kg dosageconcentration this compound possesses good COX-2 selectivity.

TABLE 1 COX-1 ACTIVITY INHIBITION - Group Averages TXB₂ Pg/mL/WellPercent Inhibition Hour 0-hour 2-hour 8-hour 2-hour 8-hour Untreated 4645 140 2% 0% 5 mg/kg 41 38 104 7% 0% COX-2 ACTIVITY INHIBITION - GroupAverages PGE₂ Pg/mL/Well Percent Inhibition Hour 0-hour 2-hour 8-hour2-hour 8-hour Untreated 420 486 501 0% 0% 5 mg/kg 711 165 350 77% 51%

COX inhibition is observed when the measured percent inhibition isgreater than that measured for untreated controls. The percentinhibition in the above table is calculated in a straightforward mannerin accordance with the following equation:${\%\quad{Inhibition}\quad\left( {2\text{-}{hour}} \right)} = \frac{\left( {{{PGE}_{2}\quad{at}\quad t} = 0} \right) - \left( {{{PGE}_{2}\quad{at}\quad t} = 2} \right)}{\left( {{{PGE}_{2}\quad{at}\quad t} = 0} \right)}$

Data Analysis

Statistical program packages, SYSTAT (SYSTAT, INC.) and StatView (AbacusCencepts, Inc.) for Macintosh were used. Differences between testcompound treated group and control group were tested for using ANOVA.The IC₅₀ (ED₃₀) values were calculated from the equation for thelog-linear regression line of concentration (dose) versus percentinhibition.

Most compounds prepared in the Working Examples as described hereinafterwere tested by at least one of the methods described above, and showedIC₅₀ values of 0.001 μM to 3 μM with respect to inhibition of COX-2 ineither the canine or human assays.

COX-2 selectivity can be determined by ratio in terms of IC₅₀ value ofCOX-1 inhibition to COX-2 inhibition. In general, it can be said that acompound showing a COX-2/COX-1 inhibition ratio of more than 5 has goodCOX-2 selectivity.

The compounds of the formula I of this invention can be administered viaoral, parenteral, anal, buccal or topical routes to mammals (includinghumans, dogs, cats, horses and livestock).

In general, these compounds are most desirably administered to humans indoses ranging from 0.01 mg to 100 mg per kg of body weight per day,although variations will necessarily occur depending upon the weight,sex and condition of the subject being treated, the disease state beingtreated and the particular route of administration chosen. However, adosage level that is in the range of from 0.1 mg to 10 mg per kg of bodyweight per day, single or divided dosage is most desirably employed inhumans for the treatment of abovementioned diseases.

These compounds are most desirably administered to said non-humanmammals, e.g. dogs, cats, horses or livestock in an amount, expressed asmg per kg of body weight of said member per day, ranging from about 0.01mg/kg to about 20.0 mg/kg/day, preferably from about 0.1 mg/kg to about12.0 mg/kg/day, more preferably from about 0.5 mg/kg to about 10.0mg/kg/day, and most preferably from about 0.5 mg/kg to about 8.0mg/kg/day.

The compounds of the present invention may be administered alone or incombination with pharmaceutically acceptable carriers or diluents byeither of the above routes previously indicated, and such administrationcan be carried out in single or multiple doses. More particularly, thenovel therapeutic agents of the invention can be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, trochees, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored.In general, the therapeutically-effective compounds of this inventionare present in such dosage forms at concentration levels ranging from 5%to 70% by weight, preferably 10% to 50% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate,dipotassium phosphate and glycine may be employed along with variousdisintegrants such as starch and preferably corn, potato or tapiocastarch, alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatine capsules; preferred materials in this connectionalso include lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various combinations thereof.

A preferred composition for dogs comprises an ingestible liquid peroraldosage form selected from the group consisting of a solution,suspension, emulsion, inverse emulsion, elixir, extract, tincture, andconcentrate, optionally to be added to the drinking water of the dogbeing treated. Any of these liquid dosage forms, when formulated inaccordance with methods well known in the art, can either beadministered directly to the dog being treated, or may be added to thedrinking water of the dog being treated. The concentrate liquid form, onthe other hand, is formulated to be added first to a given amount ofwater, from which an aliquot amount may be withdrawn for administrationdirectly to the dog or addition to the drinking water of the dog.

A preferred composition provides delayed-, sustained-, and/orcontrolled-release of said anti-inflammatory selective COX-2 inhibitor.Such preferred compositions include all such dosage forms which produce≧80% inhibition of COX-2 isozyme activity and result in a plasmaconcentration of said inhibitor of at least 3 fold the COX-2 IC₅₀ for atleast 4 hours; preferably for at least 8 hours; more preferably for atleast 12 hours; more preferably still for at least 16 hours; even morepreferably still for at least 20 hours; and most preferably for at least24 hours. Preferably, there is included within the above-describeddosage forms those which produce ≧80% inhibition of COX-2 isozymeactivity and result in a plasma concentration of said inhibitor of atleast 5 fold the COX-2 IC₅₀ for at least 4 hours, preferably for atleast 8 hours, more preferably for at least 12 hours, still morepreferably for at least 20 hours, and most preferably for at least 24hours. More preferably, there is included the above-described dosageforms which produce ≧90% inhibition of COX-2 isozyme activity and resultin a plasma concentration of said inhibitor of at least 5 fold the COX-2IC₅₀ for at least 4 hours, preferably for at least 8 hours, morepreferably for at least 12 hours, still more preferably for at least 20hours, and most preferably for at least 24 hours.

For parenteral administration, solutions of a compound of the presentinvention in either sesame or peanut oil or in aqueous propylene glycolmay be employed. The aqueous solutions should be suitably buffered(preferably pH>8) if necessary and the liquid diluent first renderedisotonic. These aqueous solutions are suitable for intravenous injectionpurposes. The oily solutions are suitable for intra-articular,intramuscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well-known to those skilled in theart. Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of creams, jellies,gels, pastes, ointments and the like, in accordance with standardpharmaceutical practice.

The compounds of formula I may also be administered in the form ofsuppositories for rectal or vaginal administration of the activeingredient. These compositions can be prepared by mixing the activeingredient with a suitable non-irritating excipient which is solid atroom temperature (for example, 10° C. to 32° C.) but liquid at therectal temperature and will melt in the rectum or vagina to release theactive ingredient. Such materials are polyethylene glycols, cocoabutter, suppository and wax.

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

For transdermal administration, transdermal patches prepared inaccordance with well known drug delivery technology may be prepared andapplied to the skin of a mammal, preferably a human or a dog, to betreated, whereafter the active agent by reason of its formulatedsolubility characteristics migrates across the epidermis and into thedermal layers of the skin where it is taken up as part of the generalcirculation, ultimately providing systemic distribution of the activeingredient over a desired, extended period of time. Also included areimplants which are placed beneath the epidermal layer of the skin, i.e.between the epidermis and the dermis of the skin of the patient beingtreated. Such an implant will be formulated in accordance with wellknown principles and materials commonly used in this deliverytechnology, and may be prepared in such a way as to provide controlled-,sustained-, and/or delayed-release of the active ingredient into thesystemic circulation of the patient. Such subepidermal (subcuticular)implants provide the same facility of installation and deliveryefficiency as transdermal patches, but without the limitation of beingsubject to degradation, damage or accidental removal as a consequence ofbeing exposed on the top layer of the patient's skin.

EXAMPLES

The following examples contain detailed descriptions of the methods ofthe preparation of compounds of formula I. These detailed descriptionsfall within the scope of the invention and serve to exemplify the abovedescribed general synthetic procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended to restrict the scope of the present invention.

The invention is illustrated in the following non-limiting examples inwhich, unless stated otherwise: all operations were carried out at roomor ambient temperature, that is, in the range of 18-25° C.; evaporationof solvent was carried out using a rotary evaporator under reducedpressure with a bath of up to 60° C.; reactions were monitored by thinlayer chromatography (TLC) and analytical column liquid chromatography,and reaction times are given for illustration only; melting points(m.p.) given are uncorrected (polymorphism may result in differentmelting points); structure and purity of all isolated compounds wereassured by at least one of the following techniques: TLC (Merck silicagel 60 F-254 precoated plates), high performance liquid chromatograpy(HPLC), or mass spectrometry. Flash column chromatography was carriedout using Merck silica gel 60 (230-400 mesh ASTM). Preparative HPLC wascarried out using Hewlett Packard 1100 Liquid Chromatography/MassSelective Detector (LC/MSD). Separation was done on a Monochrom 5μ CNcolumn PN 0509-250*212 from MetaChem Technologies. The flow rate was 20ml/min running a gradient of 0 to 90% of isopropanol in n-hexane.Low-resolution mass spectral data (EI) were obtained on an Automass 120(JEOL) mass spectrometer. Liquid Chromatography data was collected on aHewlett Packard 1100 Liquid Chromatography/Mass Selective Detector(LC/MSD). Analysis was performed on a Luna C-18 column with dimensionsof 3.0×150 mm. The flow rate was 0.425 ml/minute running a gradient of50% 0.1% aqueous formic acid and 50% acetonitrile to 100% acetonitrilein 15 minutes. The ionization type for the mass detector of the MassSpectrophotometer was atmospheric pressure electrospray in the positiveion mode with a fragmentor voltage of 50 volts.

Procedure:

Example 11-(5-Methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-5-phenyl-1H-pyrazole-4-carbonitrile

A mixture of the 2-hydrazino-5-methylsulfonyl pyridine (180 mg, 0.81mmol) and 1-benzoyl-2,2-bis(methylthio)-1-cyano ethene (201 mg, 0.81mmol) in anhydrous ethanol was refluxed overnight. The resultingsolution was cooled to room temperature, diluted with water (25 ml) andextracted with ethyl acetate (2×25 ml). The ethyl acetate layer wasdried with sodium sulfate and concentrated to give crude product.Chromatography of the mixture led to the isolation of the desiredproduct (26 mg, 9%) in the form of a white solid.

The following examples were prepared by a procedure analogous to that ofExample 1, except where indicated. LC refers to liquid chromatographyelution time (minutes) and MS refers to mass spectral peaks (AMU). Theparticular apparatus and data acquisition parameters are as definedabove.

Example 25-(4-Chloro-phenyl)-1-(5-methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-1H-pyrazole-4-carbonitrile

The title compound was prepared as in Example 1 wherein 1-(4-chlorobenzoyl)-2,2-bis(methylthio)-1-cyano ethene was used in place of wherein1-benzoyl-2,2-bis(methylthio)-1-cyano ethene. Chromatography of themixture led to the isolation of the desired product (45 mg, 24%) in theform of a white solid.

Example 31-(5-Methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-5-p-tolyl-1H-pyrazole-4-carbonitrile

The title compound was prepared as in Example 1 wherein 1-4-methylbenzoyl)-2,2-bis(methylthio)-1-cyano ethene was used in place of1-benzoyl-2,2-bis(methylthio)-1-cyano ethene. Chromatography of themixture led to the isolation of the desired product (24 mg, 14%) in theform of a pale white solid.

Example 41-(5-Methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-5-thiophen-2-yl-1H-pyrazole-4-carbonitrile

The title compound was prepared as in Example 1 wherein1-(thiophene-2-carbonyl)-2,2-bis(methylthio)-1-cyano ethene was used inplace of 1-benzoyl-2,2-bis(methylthio)-1-cyano ethene. Chromatography ofthe mixture led to the isolation of the desired product (53 mg, 30%) inthe form of a white solid.

Example 51-(5-Methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-5-m-tolyl-1H-pyrazole-4-carbonitrile

The title compound was prepared as in Example 1 wherein1-(3-methylbenzoyl)-2,2-bis(methylthio)-1-cyano ethene was used in placeof 1-benzoyl-2,2-bis(methylthio)-1-cyano ethene. Chromatography of themixture led to the isolation of the desired product (8 mg, 4.4%) in theform of a pale white solid.

Example 65-(3-Chloro-phenyl)-1-(5-methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-1H-pyrazole-4-carbonitrile

The title compound was prepared as in Example 1 wherein1-(3-chlorobenzoyl)-2,2-bis(methylthio)-1-cyano ethene was used in placeof 1-benzoyl-2,2-bis(methylthio)-1-cyano ethene. Chromatography of themixture led to the isolation of the desired product (8 mg, 4.3%) in theform of a white solid.

Example 71-(5-methanesulfonyl-pyridin-2-yl)-3-methylsulfonyl-5-phenyl-1H-pyrazole-4-carbonitrile

The title compound was prepared by reacting the compound of Example 1with meta-chloroperbenzoic acid.

Example 85-furan-2-yl-1-(5-methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-1H-pyrazole-4-carbonitrile

The title compound was prepared as in Example 1 wherein1-(furan-2-oyl)-2,2-bis(methylthio)-1-cyano ethene was used in place of1-benzoyl-2,2-bis(methylthio)-1-cyano ethene. Chromatography of themixture led to the isolation of the desired product in the form of awhite solid.

The chemical structures and molecular weights of the above Examples 1-8are tabulated below in Table 2.

TABLE 2 Example Structure MW LC MS 1

370 10.882 371 2

405 13.34 405 (M+) 406 (M + H) 3

384 12.532 385 4

376 10.71 377 5

384 12.51 385 6

405 N/A 406 7

402 N/A 403 8

360 N/A 361

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims that follow and that such claims be interpreted as broadly asis reasonable.

1. A compound of the formula

wherein

is a heterocycle selected frem the group consisting of

m is 0, 1 or 2; X is CR⁷; R¹ is hydrogen, halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, formyl, formamidyl, cyano, nitro, hydroxycarbonyl,(C₁-C₆)alkoxycarbonyl, (C₂-C₉)heteroarylcarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₂-C₉)heteroarylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, or (C₁-C₆)alkylcarbonyl-N(R²)—;wherein each of said R¹ (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy; R² is hydrogen or (C₁-C₆)alkyl; R³ is(C₁-C₆)alkylthio, (C₃-C₇)carbocyclylthio, C₆-C₁₀)arylthio,(C₂-C₉)heteroarylthio, (C₁-C₆)alkyl-S(═O), (C₆-C₁₀)aryl-S(═O),(C₂-C₉)heteroaryl-S(═O), (C₁-C₆)alkyl-SO₂—, (C₆-C₁₀)aryl-SO₂—,(C₂-C₉)heteroaryl-SO₂—, (C₁-C₆)alkyl-SO₂-amino,(C₃-C₇)carbocyclyl-SO₂—amino, (C₆-C₁₀)aryl-SO₂-amino,(C₂-C₉)heteroaryl-SO₂-amino, amino-SO₂—, N—(C₁-C₆)alkylamino-SO₂—,N,N—[(C₁-C₆)alkyl]₂amino-SO₂—, N—(C₃-C₇)carbocyclylamino-SO₂—,N—(C₆-C₁₀)arylamino-SO₂—, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino-SO₂—,N—(C₂-C₉)heteroarylamino-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino orN—(C₂-C₉)heteroarylamino; wherein each of said R³ (C₁-C₆)alkyl groupwherever they occur may optionally be substituted with one to threesubstituents independently selected from the group consisting of halo,hydroxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, carbonyl, formyl, formamidyl, (C₁-C₆)alkylcarbonyl,cyano, mercapto, nitro, hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy; R⁴ is (C₁-C₆)alkyl optionally substituted byhydroxy or by one to three halo atoms; R⁵ is hydrogen, halo, hydroxy,mercapto, (C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted with one tothree halogen atoms, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,cyano, formyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylcarbonyloxy,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino N—(C₆-C₁₀)arylaminoN—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido, or(C₂-C₆)alkylthio; wherein each of said R⁵ (C₁-C₆)alkyl group wbereverthey occur may optionally be substituted with one to three substituontsindependently selected from the group consisting of halo, hydroxy,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy,carbonyl, formyl, formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto,nitro, hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy; R⁶ is selected from the group consisting of:(a) phenyl optionally substituted by one to three substituentsindependently selected from the group consisting of halo, hydroxy,cyano, mercapto, hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃,(C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; (b) phenyl fused to a saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring; whereineither of said phenyl or said fused saturated, partially saturated oraromatic (5- to 7-membered)-carbocyclic ring is optionally substitutedby one to two substituents per ring, wherein said substituents areindependently selected from the group consisting of halo, hydroxy,cyano, mercapto, hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃,(C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino,N—(C₂-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)hcterocyclyl; (c) phenyl fused to a saturated, partiallysaturated or aromatic (5- to 6-membered)-heterocyclyl containing one totwo ring heteroatoms independently selected from the group consisting of—N═, —NR²—, —S— and —O—; wherein either of said phenyl or said fusedsaturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is optionally substituted with one to twosubstituents per ring; wherein said substituents are independentlyselected from tbe group consisting of halo, hydroxy, cyano, mercapto,hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N-[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbacyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; (d) (3- to 7-membered)-carbocyclic optionallycontaining one or two double bonds; wherein said (3- to7-membered)-carbocyclic may also be optionally substituted by one tothree substituents independently selected from the group consisting ofhalo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy,—OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; (e) (5- to 7-membered)-carbocyclic fused to asaturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring; wherein said (5- to7-membered)-carbocyclic may optionally contain one or two double bonds;wherein either of said (5- to 7-membered)-carbocyclic or said fusedsaturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring is optionally substituted by one to twosubstituents per ring, wherein said substituents are independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)calbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarborlyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; (f) (5- to 7-membered)-carbocyclic fused to asaturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the group consisting of —N═, —NR²—, —S— and—O—; wherein said (5- to 7-membered)-carbocyclic may optionally containone or two double bonds; wherein either of said (5- to7-membered)-carbocyclic or said fused saturated, partially saturated oraromatic (5- to 6-membered)-heterocyclyl is optionally substituted withone to two substituents per ring; wherein said substituents areindependently selected from the group consisting of halo, hydroxy,cyano, mercapto, hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃,(C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylaminoN—(C₆-C₁₀)arylamino N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino amido, N—(C₁-C₆)alkylamidoN,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; (g) saturated, partially saturated or aromatic (5-to 6-membered)-heterocyclyl containing one to four ring heteroatomsindependently selected from the groups consisting of —N═, —NR²—, —O—,and —S—; wherein said (5- to 6-membered)-heterocyclyl is optionallysubstituted by one to three substituents independently selected from thegroup consisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl,nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; (h) saturated, partially saturated or aromatic (5-to 6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the group consisting of —N═, —NR²—, —S— and—O—; wherein said saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is fused to a saturated, partially saturated oraromatic (5- to 7-membered)-carbocyclic ring; wherein either of saidsaturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl ring or said fused saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring is optionallysubstituted by one to two substituents per ring; wherein saidsubstituents are independently selected from the group consisting ofhalo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy,—OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; and (i) saturated, partially saturated or aromatic(5- to 6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the group consisting of —N═, —NR²—, —S—, and—O—; wherein said saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is fused to a saturated, partially saturated oraromatic (5- to 6-membered)-heterocyclyl containing one to two ringheteroatoms independently selected from the group consisting of —N═,—NR²—, —S— and —O—; wherein either of said saturated, partiallysaturated or aromatic (5- to 6-membered)-heterocyclyl or said fusedsaturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is optionally substituted with one to twosubstituents per ring; wherein said substituents are independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylanuno,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; wherein each of said R¹ (a), (b), (c), (d), (e),(f), (g), (h), or (i) (C₁-C₆)alkyl group wherever they occur mayoptionally be substituted with one to three substituents independentlyselected from the group consisting of halo, hydroxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, carbonyl, formyl,formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto, nitro,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)hcteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₉)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy; R⁷ is hydrogen, halo, hydroxy, mercapto,(C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted with one to threehalogen atoms, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,cyano, formyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylcarbonyloxy,hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido, nitro, or(C₁-C₆)alkylthio; wherein each of said R⁷ (C₁-C₆)alkyl group whereverthey occur may optionally be substituted with one to three substituentsindependently selected from the group consisting of halo, hydroxy,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy,carbonyl, formyl, formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mexcapto,nitro, hydroxycarbonyl, (C₁-C₆)alkoxycaxbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroalyl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy; or a pharmaceutically acceptAble salt thereof.2. A compound according to claim 1 wherein said compound has the formula

wherein X is CR⁷; and m is
 2. 3. A compound according to claim 1 whereinsaid compound has the formula

wherein X is CR⁷; and m is
 2. 4. A compound according to claim 1 whereinR⁶ is (a) phenyl optionally substituted by one to three substituentsindependently selected from the group consisting of halo, hydroxy,cyano, mercapto, hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃,(C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; wherein each of said R⁶ (a) (C₁-C₆)alkyl groupwherever they occur may optionally be substituted with one to threesubstituents independently selected from the group consisting of halo,hydroxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, carbonyl, formyl, fonnamidyl, (C₁-C₆)alkylcarbonyl,cyano, mercapto, nitro, hydroxycarbonyl, (C₁-C₆)allcoxycarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.
 5. A compound according to claim 1 wherein R⁶is (b) phenyl fused to a saturated, partially saturated or aromatic (5-to 7-membered)-carbocyclic ring; wherein either of said phenyl or saidfused saturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring is optionally substituted by one to twosubstituents per ring, wherein said substituents are independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; wherein each of said R⁶ (b) (C₁-C₆)alkyl groupwherever they occur may optionally be substituted with one to threesubstituents independently selected from the group consisting of halo,hydroxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, carbonyl, formyl, formamidyl, (C₁-C₆)alkylcarbonyl,cyano, mercapto, nitro, hydroxycaxbonyl, (C₁-C₆)alkoxycarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.
 6. A compound according to claim 1 wherein R⁶is (c) phenyl fused to a saturated, partially saturated or aromatic (5-to 6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the group consisting of —N═, —NR²—, —S— and—O—; wherein either of said phenyl or said fused saturated, partiallysaturated or aromatic (5- to 6-membered)-heterocyclyl is optionallysubstituted with one to two substituents per ring; wherein saidsubstituents are independently selected from the group consisting ofhalo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy,—OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; wherein each of said R⁶ (c) (C₁-C₆)alkyl groupwherever they occur may optionally be substituted with one to threesubstituents independently selected from the group consisting of halo,hydroxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyctyl,(C₁-C₆)alkoxy, carbonyl, formyl, formamidyl, (C₁-C₆)alkylcarbonyl,cyano, mercapto, nitro, hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.
 7. A compound according to claim 1 wherein R⁶is (d) (3- to 7-membered)-carbocycuc optionally containing one or twodouble bonds; wherein said, (3- to 7-membered)-carbocyclic may also beoptionally substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, cyano, mereapto,hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)hetcrocyclyl; wherein each of said R⁶ (d) (C₁-C₆)alkyl groupwherever they occur may optionally be substituted with one to threesubstituents independently selected from the group consisting of halo,hydroxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, carbonyl, formyl, formamidyl, (C₁-C₆)alkylcarbonyl,cyano, mercapto, nitro, hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alky]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryolxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkythio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.
 8. A compound according to claim 1 wherein R⁶is (e) (5- to 7-membered)-carbocyclic fused to a saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring; wherein said(5- to 7-membered)-carbocyclic may optionally contain one or two doublebonds; wherein either of said (5- to 7-membered)-carbocyclic or saidfused saturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring is optionally substituted by one to twosubstituents per ring, wherein said substituents are independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylammo, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; wherein each of said R⁶ (e) (C₁-C₆)alkyl groupwherever they occur may optionally be substituted with one to threesubstituents independently selected from the group consisting of halo,hydroxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, carbonyl, formyl, formamidyl, (C₁-C₆)alkylcarbonyl,cyano, mercapto, nitro, hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heceroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.
 9. A compound according to claim 1 wherein R⁶is (f) (5- to 7-membered)-carbocyclic fused to a saturated, partiallysaturated or aromatic (5- to 6-membered)-heterocyclyl containing one totwo ring heteroatoms independently selected from the group consisting of—N═, —NR²—, —S— and —O—; wherein said (5- to 7-membered)-carbocyclic mayoptionally contain one or two double bonds; wherein either of said (5-to 7-membered)-carbocyclic or said fused saturated, partially saturatedor aromatic (5- to 6-membered)-heterocyclyl is optionally substitutedwith one to two substituents per ring; wherein said substituents areindependently selected from the group consisting of halo, hydroxy,cyano, mercapto, hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃,(C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; wherein each of said R⁶ (f) (C₁-C₆)alkyl groupwherever they occur may optionally be substituted with one to threesubstituents independently selected from the group consisting of halo,hydroxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, carbonyl, formyl, formamidyl, (C₁-C₆)alkylcaxbonyl,cyano, mercapto, nitro, hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.
 10. A compound according to claim 1 wherein R⁶is (g) saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl containing one to four ring heteroatomsindependently selected from the groups consisting of —N═, —NR²—, —O—,and —S—; wherein said (5- to 6-membered)-heterocyclyl is optionallysubstituted by one to three substituents independently selected from thegroup consisting of halo, hydroxy, cyano, mercapto, hydroxycarbonyl,nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; wherein each of said R⁶ (g) (C₁-C₆)alkyl groupwherever they occur may optionally be substituted with one to threesubstituents independently selected from the group consisting of halo,hydroxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, carbonyl, formyl, formamidyl, (C₁-C₆)alkylcarbonyl,cyano, mercapto, nitro, hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.
 11. A compound according to claim 1 wherein R⁶is (h) saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the group consisting of —N═, —NR²—, —S— and—O—; wherein said saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is fused to a saturated, partially saturated oraromatic (5- to 7-membered)-carbocyclic ring; wherein either of saidsaturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl ring or said fused saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring is optionallysubstituted by one to two substituents per ring; wherein saidsubstituents are independently selected from the group consisting ofhalo, hydroxy, cyano, mercapto, hydroxycarbonyl, nitro, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy,—OCF₃, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; wherein each of R⁶ (h) (C₁-C₆)alkyl group whereverthey occur may optionally be substituted with one to three substituentsIndependently selected from the group consisting of halo, hydroxy,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy,carbonyl, formyl, formamidyl, (C₁-C₆)alkylcarbonyl, cyano, mercapto,nitro, hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO_(2—, (C) ₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.
 12. A compound according to claim 1 wherein R⁶is (i) saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the group consisting of —N═, —NR²—, —S—, and—O—; wherein said saturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is fused to a saturated, partially saturated oraromatic (5- to 6-membered)-heterocyclyl containing one to two ringheteroatoms independently selected from the group consisting of —N═,—NR²—, —S— and —O—; wherein either of said saturated, partiallysaturated or aromatic (5- to 6-membered)-heterocyclyl or said fusedsaturated, partially saturated or aromatic (5- to6-membered)-heterocyclyl is optionally substituted with one to twosubstituents per ring; wherein said substituents are independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,hydroxycarbonyl, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocyclyl, (C₁-C₆)alkoxy, —OCF₃, (C₁-C₆)alkylthio,(C₁-C₆)alkyl-S(═O)—, (C₁-C₆)alkyl-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino,N—(C₂-C₉)heteroarylamino, amido, N—(C₁-C₆)alkylamido,N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N-(C₆-C₁₀)arylamido, N—(C₁-C₆)alkoxyamido,(C₁-C₆)alkylcarbonyloxy, (C₁-C₆)alkylcarbonyl-N(R²)—, formyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl and(C₂-C₉)heterocyclyl; wherein each of said R⁶ (i) (C₁-C₆)alkyl groupwherever they occur may optionally be substituted with one to threesubstituents independently selected from the group consisting of halo,hydroxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocyclyl,(C₁-C₆)alkoxy, carbonyl, formyl, formamidyl, (C₁-C₆)alkylcarbonyl,cyano, mercapto, nitro, hydroxycarbonyl, (C₁-C₆)alkoxycarbonyl, amino,N—(C₁-C₆)alkylamino, N,N—[(C₁-C₆)alkyl]₂amino,N—(C₃-C₇)carbocyclylamino, N—(C₆-C₁₀)arylamino,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, N—(C₂-C₉)heteroarylamino, amido,N—(C₁-C₆)alkylamido, N,N—[(C₁-C₆)alkyl]₂amido, N—(C₆-C₁₀)arylamido,N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamido, (C₁-C₆)alkoxyamido, (C₆-C₁₀)aryl,(C₆-C₁₀)aryolxy, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroarylcarbonyl, (C₁-C₆)alkylthio, (C₁-C₆)alkyl-S(═O)—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkylcarbonyl-N(R²)—, and(C₁-C₆)alkylcarbonyloxy.
 13. A compound according to claim 1 wherein R⁶is phenyl optionally substituted with one to three halo or one to three(C₁-C₆)alkyl.
 14. A compound according to claim 1 wherein R⁶ is aromatic(5- to 6-membered)-heterocyclyl containing one to two ring heteroatomsindependently selected from the groups consisting of —N═, —NR²—, —O—,and —S—; wherein said (5- to 6-membered)-heterocyclyl is optionallysubstituted by one to three halo or one to three (C₁-C₆)alkyl.
 15. Acompound according to claim 1 wherein R¹ is hydrogen, halo, cyano, or(C₁-C₆)alkylcarbonyl.
 16. A compound according to claim 1 wherein R¹ iscyano.
 17. A compound according to claim 1 wherein R³ is(C₁-C₆)alkylthio, (C₃-C₇)carbocyclylthio, C₆-C₁₀)arylthio,(C₂-C₉)heteroarylthio, (C₁-C₆)alkyl-S(═O), (C₆-C₁₀)aryl-S(═O),(C₂-C₉)heteroaryl-S(═O), (C₁-C₆)alkyl-SO₂—, (C₆-C₁₀)aryl-SO₂—,(C₂-C₉)heteroaryl-SO₂—, (C₁-C₆)alkyl-SO₂-amino,(C₃-C₇)carbocyclyl-SO₂-amino, (C₆-C₁₀)aryl-SO₂-amino,(C₂-C₉)heteroaryl-SO₂-amino, amino-SO₂—, N—(C₁-C₆)alkylamino-SO₂,N,N—[(C₁-C₆)alkyl]₂amino-SO₂—, N—(C₃-C₇)carbocyclylamino-SO₂—,N—(C₆-C₁₀)arylamino-SO₂—, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino-SO₂—,N—(C₂-C₉)heteroarylamino-SO₂—, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, orN—(C₂-C₉)heteroarylamino.
 18. A compound according to claim 1 wherein R³is C₁-C₆)alkylthio, (C₃-C₇)carbocyclylthio, C₆-C₁₀)arylthio,(C₂-C₉)heteroarylthio, amino, N—(C₁-C₆)alkylamino,N,N—[(C₁-C₆)alkyl]₂amino, N—(C₃-C₇)carbocyclylamino,N—(C₆-C₁₀)arylamino, N—(C₁-C₆)alkyl-N—(C₆-C₁₀)arylamino, orN—(C₂-C₉)heteroarylamino.
 19. A compound according to claim 1 wherein R³is (C₁-C₆)alkylthio or amino.
 20. A compound according to claim 1wherein R⁴ is (C₁-C₆)alkyl optionally substituted by one to three haloatoms.
 21. A compound according to claim 1 wherein R⁴ is methyl.
 22. Acompound according to claim 1 wherein said compound is selected from thegroup consisting of:1-(5-Methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-5-phenyl-1H-pyrazole-4-carbonitrile;5-(4-Chloro-phenyl)-1-(5-methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-1H-pyrazole-4-carbonitrile;1-(5-Methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-5-p-tolyl-1H-pyrazole-4-carbonitrile;1-(5-Methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-5-thiophen-2-yl-1H-pyrazole-4-carbonitrile;1-(5-Methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-5-m-tolyl-1H-pyrazole-4-carbonitrile;5-(3-Chloro-phenyl)-1-(5-methanesulfonyl-pyridin-2-yl)-3-methylsulfanyl-1H-pyrazole-4-carbonitrile;3-Methanesulfonyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazole-4-carbonitrile;3-Azido-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazole-4-carbonitrile;3-Amino-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazole-4-carbonitrile;N-[4-Cyano-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazol-3-yl]-methanesulfonamide;[4-Cyano-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazol-3-ylamino]-aceticacid;[4-Cyano-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazol-3-ylamino]-aceticacid methyl ester;1-(6-Methanesulfonyl-pyridin-3-yl)-3-methylsulfonyl-5-phenyl-1H-pyrazole-4-carbonitrile;3-Methanesulfonyl-1-(6-methanesulfonyl-pyridin-3-yl)-5-phenyl-1H-pyrazole-4-carbonitrile;3-Methanesulfonyl-1-(6-methanesulfonyl-pyridin-3-yl)-5-phenyl-1H-pyrazole-4-carbonitrile;or a pharmaceutically acceptable salt thereof.
 23. A pharmaceuticalcomposition for the treatment of a condition selected from the groupconsisting of arthritis, fever, menstrual cramps, inflammatory boweldisease, Crohn's disease, asthma, bronchitis, chronic obstructivepulmonary disease, tissue ulceration, peptic ulcers, gastritis, regionalenteritis, ulcerative colitis, recurrent gastrointestinal lesion,gastrointestinal bleeding, ocular angiogenesis, corneal injury, maculardegeneration, conjunctivitis, abnormal wound healing, skin disorders,myasthenia gravis, polymyositis, myositis, bursitis, burns, andpremature labor in a mammal, comprising an amount of a compound of claim1 or a pharmaceutically acceptable salt thereof effective in suchtreatments and a pharmaceutically acceptable carrier.
 24. A method fortreating a condition selected from the group consisting of arthritis,fever, menstrual cramps, inflammatory bowel disease, Crohe's disease,asthma, bronchitis, chronic obstructive pulmonary disease, tissueulceration, peptic ulcers, gastritis, regional enteritis, ulcerativecolitis, recurrent gastrointestinal lesion, gastrointestinal bleeding,ocular angiogenesis, corneal injury, macular degeneration,conjunctivitis, abnormal wound healing, skin disorders, myastheniagravis, polymyositis, myositis, bursitis, burns, corneal scarring, andpremature labor in a mammal, comprising administering to said mammal anamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof effective in treating such a condition.